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Department of Neurology | Department of Molecular and Human Genetics | Center for Alzheimer's and Neurodegenerative Diseases | |
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Publications
Papers 2026 
Zhao P, El Fadel O, Le A, Mangleburg CG, Dhindsa J, Wu T, Zhao J, Huang M, Amoh B, Marella AS, Li Y, Seyfried NT, Levey AI, Liu Z, Al-Ramahi I, Botas J, Shulman JM. Systems genetic dissection of brain gene expression reveals excitotoxic mechanisms of Alzheimer's disease. https://pubmed.ncbi.nlm.nih.gov/41691109/ Molecular Psychiatry. 2021 Jan 6; 7(2). PDF AbstractGene expression changes likely mediate the impact of Alzheimer's disease (AD) neuropathology on cognition, but there are challenges to resolve the proximal causal pathways from postmortem brain transcriptome profiles which lack temporal resolution and are further confounded by mixed pathologies. Here, we functionally dissect 30 AD-associated human brain gene co-expression modules using fruit fly (Drosophila melanogaster) models. Integrating longitudinal RNA-sequencing and behavioral phenotyping, we interrogated the consequences of amyloid beta (Aβ) plaques, tau neurofibrillary tangles, and aging, highlighting hundreds of conserved, differentially expressed genes. To pinpoint causal modules and drivers, we manipulated 344 prioritized targets in vivo, identifying 141 modifiers of Aβ- or tau-induced neurodegeneration. We discovered an upregulated immune module enriched for AD risk variants that promotes neurodegeneration based on genetic manipulations in neurons. By contrast, a downregulated human brain synaptic regulatory network includes many loss-of-function suppressors of Aβ/tau and modulates glutamatergic hyperexcitation injury. Additional analyses support a biphasic model in which early AD pathology activates expression of a synaptic transcriptional signature that promotes neuronal injury, followed by a decrease that is compensatory. In sum, our cross-species strategy establishes a causal chain linking AD pathology, transcriptome perturbation, N-Methyl-D-Aspartate receptor excitotoxicity, and neurodegeneration. Gu M, Zhao J, Deng M, Lin G, Pan X, Lin W, Ma M, Kim J, Byeon SK, Pandey A, Lange LM, Shaw CA, Kim J, Trinh J, Klein C, Kanca O, Shulman JM, Bellen HJ. Two lysosomal genes ATP13A2 and GBA1 interact to drive neurodegeneration. https://pubmed.ncbi.nlm.nih.gov/41618357/ Molecular Neurodegeneration. 2026 Jan 30. PDF AbstractBackground Methods Results Conclusions De-Paula RB, Kim J, Rhinn H, Saade H, Chavez F, Segura T, Lozano MV, Etoundi M, Silos K, Korchina V, Doddapaneni H, Venner E, Masdeu JC, Pavlik V, Yu MM, Lin CR, Jankovic J, Buchman AS, Muzny D, Gibbs RA, Elsea SH, Abeliovich A, Lansbury P, Vanegas-Arroyave N, Shaw CA, Shulman JM. Mapping the causal chain from genetic risk variants to lipid dysmetabolism in Parkinson's disease. https://pubmed.ncbi.nlm.nih.gov/41627849/ Brain. 2026 Feb 2. PDF AbstractThe molecular pathways linking genetic variants to Parkinson’s disease (PD) onset and progression remain incompletely defined; however, risk alleles in multiple genes, including GBA1, strongly implicate lipid metabolism. To systematically identify causal biomarker signatures, we analyzed comprehensive metabolome profiles from blood plasma in 149 PD patients and 150 controls, along with complementary genetic, RNA-sequencing, and metabolic data from other available clinical and pathologic cohorts. Using colocalization and summary-data-based Mendelian randomization, we tested whether expression and metabolic quantitative trait loci mediate the association between implicated genetic variants and PD risk. We further integrated differential metabolomics and proteomics from blood and brain to reveal pertinent mechanisms. We show that common PD risk variants at the serine palmitoyltransferase small subunit B (SPTSSB) locus, a key regulator of de novo sphingolipid biosynthesis, are associated with increased SPTSSB brain expression and elevated plasma ceramides. Additional analyses strongly support our hypothesis that a common SPTSSB causal variant is responsible for PD risk as well as the expression and metabolic quantitative trait loci. Multiple sphingolipids and fatty acid derivatives were perturbed in PD, and we identified both unique and shared features with the Alzheimer’s disease metabolome. A PD acylcarnitine signature was further replicated in human postmortem brain tissue, when comparing those with or without preclinical Lewy body pathology. Integrated analysis of complementary brain proteomic profiles revealed dysregulation of mitochondrial processes dependent on acylcarnitines, including fatty acid beta-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation. Our results identify promising biomarkers and reveal a causal chain linking genetic variation to altered gene/protein expression, lipid dysmetabolism, and the manifestation of PD. Bereshneh AH, Wilson KA, Pan X, Hannan SB, Cooper MA, Diaz J, Leon E, Moses TM, Azamian MS, Scott DA, Au PYB, Appendino JP, Scheffer IE, Kaspi A, Bahlo M, Hildebrand MS, Morgan AT, Ekure E; Baylor College of Medicine Center for Precision Medicine Models; Shulman JM, Hildebrandt F, Posey JE, Kruszka P, Vilain E, Yamamoto S, Kanca O, Berger S, Bellen HJ. Rare heterozygous de novo variants in RAPGEF2 are associated with a neurodevelopmental disorder. https://pubmed.ncbi.nlm.nih.gov/41556274/ Genetics in Medicine. 2026 Jan 16. AbstractPurpose: RAPGEF2 encodes a guanine nucleotide exchange factor (GEF) that activates small GTPases and has not been linked to a Mendelian disorder. RAPGEF2 is highly intolerant to loss-of-function variants. We report five de novo heterozygous variants in RAPGEF2 in unrelated individuals with developmental delay, attention deficit hyperactivity disorder, epilepsy, dysmorphic features, or other manifestations. We used a Drosophila model to assess the functional impact of the identified human variants. Methods: We generated a Kozak-GAL4 null allele of the Drosophila ortholog of RAPGEF2, PDZ-GEF, and used the allele to determine the gene expression pattern as well as the LoF phenotypes. We expressed the reference and variant RAPGEF2 in PDZ-GEF mutant background to conduct “humanization” studies. Results: Our experiments show that PDZ-GEF is expressed in the central nervous system. Loss of PDZ-GEF leads to severe locomotion defects, aberrant microtubular stability in motor neuron axons, and synaptic overgrowth at neuromuscular junctions in third instar larvae. Mutant animals are lethal at various developmental stages. Importantly, the neurodevelopmental phenotypes can be rescued by expression of the human RAPGEF2 reference cDNA but not by any of the variants. Conclusion: Our findings provide functional evidence that the tested RAPGEF2 variants are LoF alleles and that the RAPGEF2 variants are associated with a neurodevelopmental disorder. 2025 Kim J, Shulman JM. Pleiotropy and the Increasing Complexity of Parkinson's Disease Genetics. https://pubmed.ncbi.nlm.nih.gov/40944491/ Annals of Neurology. 2025 Sep 13; 98(5). PDF Shaw CA, Williams CJ, Tan T, Illera D, Di N, Shulman JM, Belmont JW. The Causal Pivot: A structural approach to genetic heterogeneity and variant discovery in complex diseases. https://pubmed.ncbi.nlm.nih.gov/40829599/ American Journal of Human Genetics. 2025 Sep 4; 112(9). PDF AbstractWe present the Causal Pivot (CP) as a structural causal model (SCM) for analyzing genetic heterogeneity in complex diseases. The CP leverages an established causal factor or factors to detect the contribution of additional suspected causes. Specifically, polygenic risk scores (PRSs) serve as known causes, while rare variants (RVs) or RV ensembles are evaluated as candidate causes. The CP incorporates outcome-induced association by conditioning on disease status. We derive a conditional maximum-likelihood procedure for binary and quantitative traits and develop the Causal Pivot likelihood ratio test (CP-LRT) to detect causal signals. Through simulations, we demonstrate the CP-LRT's robust power and superior error control compared to alternatives. We apply the CP-LRT to UK Biobank (UKB) data, analyzing three exemplar diseases: hypercholesterolemia (HC, low-density lipoprotein cholesterol ≥4.9 mmol/L; nc = 24,656), breast cancer (BC, ICD-10 C50; nc = 12,479), and Parkinson disease (PD, ICD-10 G20; nc = 2,940). For PRS, we utilize UKB-derived values, and for RVs, we analyze ClinVar pathogenic/likely pathogenic variants and loss-of-function mutations in disease-relevant genes: LDLR for HC, BRCA1 for BC, and GBA1 for PD. Significant CP-LRT signals were detected for all three diseases. Cross-disease and synonymous variant analyses serve as controls. We further develop ancestry adjustment using matching and inverse probability weighting as well as regression and doubly robust methods; we extend this to examine oligogenic burden in the lysosomal storage pathway in PD. The CP reveals an approach to address heterogeneity and is an extensible method for inference and discovery in complex disease genetics. Lange LM, Fang ZH, Screven L, Tan AH, Alcalay RN, Amouri R, Bovenzi R, Fenn M, Frost JLI, Jankovic J, Jasaityte S, Jaunmuktane Z, Jeon B, Sarmiento IJK, Krüger R, Kuhlenbäumer G, Lin CH, Pavelka L, Periñan MT, Sassi SB, Schirinzi T, Shin JH, Shulman JM, Tay YW, Uitti R, Warner T, Wszolek ZK, Wu L, Wu RM, Zeuner KE, Blauwendraat C, Singleton A, Mencacci NE, Morris HR, Lim SY, Lohmann K, Klein C; Global Parkinson's Genetics Program (GP2). Rare but Relevant? Assessing Variants in Dystonia-Linked Genes in Parkinson's Disease. https://pubmed.ncbi.nlm.nih.gov/41074695/ Movement Disorders. 2025 Jul 11. AbstractBackground: Dystonia and Parkinson's disease (PD) exhibit clinical and genetic overlap, but the relevance of dystonia gene variants in PD remains unclear. Objective: The aim was to assess the frequency of dystonia-linked pathogenic variants in PD. Methods: We screened sequencing data from 15,684 individuals (8272 PD, 3200 atypical parkinsonism, and 4212 unaffected) from the Global Parkinson's Genetics Program (GP2) and Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) for variants in genes linked to isolated dystonia, dystonia-parkinsonism, and myoclonus-dystonia. Results: Pathogenic variants were identified only in PD patients. Forty-five PD individuals (0.54%) carried 26 distinct (likely) pathogenic variants in nine dystonia-linked genes, most frequently in GCH1, followed by VPS16. Conclusion: Though rare, pathogenic variants in dystonia-linked genes are present in clinically and pathologically diagnosed PD. Our results reinforce GCH1 as a PD-relevant gene with clinical implications, whereas variants identified in other genes are rare and of uncertain relation to the PD phenotype. 
Ma L, Kanca O, Goodman LD, Hannan SB, Strohlein CE, Tyrlik M, Liu Z, Bellen HJ, Shulman JM. Haploinsufficiency of ITSN1 and SYNJ1, but not SYNJ2, disrupts endolysosomal morphology and exacerbates alpha-synuclein pathology in Drosophila. https://pubmed.ncbi.nlm.nih.gov/40056900/ Movement Disorders. 2025 Mar 25; 44(3). AbstractDespite its significant heritability, the genetic basis of Parkinson's disease (PD) remains incompletely understood. Here, in analyzing whole-genome sequence data from 3,809 PD cases and 247,101 controls in the UK Biobank, we discover that protein-truncating variants in ITSN1 confer a substantially increased risk of PD (p = 6.1 × 10-7; odds ratio [95% confidence interval] = 10.5 [5.2, 21.3]). We replicate this association in three independent datasets totaling 8,407 cases and 413,432 controls (combined p = 4.5 × 10-12). Notably, ITSN1 haploinsufficiency has also been associated with autism spectrum disorder, suggesting variable penetrance/expressivity. In Drosophila, we find that loss of the ITSN1 ortholog Dap160 exacerbates α-synuclein-induced neuronal toxicity and motor deficits, and in vitro assays further suggest a physical interaction between ITSN1 and α-synuclein. These results firmly establish ITSN1 as a PD risk gene with an effect size exceeding previously established loci, implicate vesicular trafficking dysfunction in PD pathogenesis, and potentially open new avenues for therapeutic development. Malek J, Levchenko A, Robinson JO, Fong J, Lin CR, Jackson GR, Blumenthal-Barby J, Shulman JM, McGuire AL. Dilemmas in diagnosing Alzheimer's disease: The peril and promise of self-fulfilling prophecies. https://pubmed.ncbi.nlm.nih.gov/40255038/ Journal of Alzheimer's Disease. 2025 Jun; 105(3). AbstractTo date, there are limited empirical data to inform various approaches to communication with patients receiving information on Alzheimer's disease (AD) risk or diagnosis during the pre-symptomatic or minimally symptomatic stages. This article explores the ethical implications of psychological responses known as self-fulfilling prophecies that may impact cognitive decline among individuals diagnosed with or at risk for AD. We describe questions these potential effects raise about the ways clinicians communicate with patients, as well as how caregivers may interact with patients. Recent advancements in biomarkers and treatment for AD underscore the urgency of understanding these phenomena and developing appropriate responses. Deger JM, Hannan SB, Gu M, Strohlein CE, Goodman LD, Pasupuleti S, Shaik Z, Ma L, Li Y, Li J, Stephens MC, Tyrlik M, Liu Z, Al-Ramahi I, Botas J, Shaw CA, Kanca O, Bellen HJ, Shulman JM. Revealing the nervous system requirements of Alzheimer disease risk genes in Drosophila. https://pubmed.ncbi.nlm.nih.gov/41167194/ American Journal of Human Genetics. 2025 Dec 4; 112(12). PDF AbstractMost Alzheimer disease (AD) susceptibility genes have poorly understood roles in the central nervous system (CNS). To address this gap, we systematically characterized 100 conserved candidate AD risk genes using a cross-species strategy in the fruit fly, Drosophila melanogaster. Genes were prioritized based primarily on human functional genomic evidence. We generated custom loss-of-function alleles for each of the conserved fly orthologs. Most of the genes are expressed in the adult brain, including 24 neuron- and 13 glia-specific expression patterns. Overall, we identify 50 candidate AD risk gene homologs with requirements for CNS structure or function, including 18 whose loss of function causes neurodegeneration (e.g., Snx6/SNX32 and ClC-a/CLCN1), 35 required for neurophysiology (e.g., Arr1/ARRB2 and stai/STMN4), and eight with diminished CNS resilience following a thermal or mechanical stress (e.g., cindr/CD2AP and Amph/BIN1). In a parallel screen, we found 28 AD risk gene homologs (e.g., Ets98B/SPI1 and Yod1/YOD1) that modify the neurotoxicity of either amyloid-β peptide or tau protein, which aggregate to form AD pathology. To translate our findings back to human AD, we used oligogenic risk scores based on gene clusters with shared nervous system phenotypes in flies, pinpointing functional pathways that differentially drive AD risk. Our results available online via the Alzheimer's Locus Integrative Cross-species Explorer portal reveal nervous system requirements for dozens of AD risk genes and may enable dissection of causal heterogeneity in AD. 2024 Pavešković M, De-Paula RB, Ojelade SA, Tantry EK, Kochukov MY, Bao S, Veeraragavan S, Garza AR, Srivastava S, Song S-Y, Fujita M, Duong DM, Bennett DA, De Jager PL, Seyfried NT, Dickinson ME, Heaney JD, Arenkiel BR, Shulman JM. Alzheimer's disease risk gene CD2AP is a dose-sensitive determinant of synaptic structure and plasticity https://pubmed.ncbi.nlm.nih.gov/39146503/ Human Molecular Genetics. 2024 Oct 15; 33(20). PDF AbstractCD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in the brain revealed no gross behavioral deficits in either 3.5- or 12-month-old mice, Cd2ap heterozygous mice demonstrated subtle impairments in discrimination learning using a touchscreen task. Based on unbiased proteomics, partial or complete loss of Cd2ap triggered perturbation of proteins with roles in protein folding, lipid metabolism, proteostasis, and synaptic function. Overall, our results reveal conserved, dose-sensitive requirements for CD2AP in the maintenance of neuronal structure and function, including synaptic homeostasis and plasticity, and inform our understanding of possible cell-type specific mechanisms in Alzheimer's Disease. 2023 
Li J, Amoh BK, McCormick E, Tarkunde A, Zhu KF, Perez A, Mair M, Moore J, Shulman JM, Al-Ramahi I, Botas J. Integration of transcriptome-wide association study with neuronal dysfunction assays provides functional genomics evidence for Parkinson's disease genes https://pubmed.ncbi.nlm.nih.gov/36173927/ . Human Molecular Genetics. 2023 Feb 15; 32(4). PDF AbstractGenome-wide association studies (GWAS) have markedly advanced our understanding of the genetics of Parkinson's disease (PD), but they currently do not account for the full heritability of PD. In many cases it is difficult to unambiguously identify a specific gene within each locus because GWAS does not provide functional information on the identified candidate loci. Here we present an integrative approach that combines transcriptome-wide association study (TWAS) with high-throughput neuronal dysfunction analyses in Drosophila to discover and validate candidate PD genes. We identified 160 candidate genes whose misexpression is associated with PD risk via TWAS. Candidates were validated using orthogonal in silico methods and found to be functionally related to PD-associated pathways (i.e. endolysosome). We then mimicked these TWAS-predicted transcriptomic alterations in a Drosophila PD model and discovered that 50 candidates can modulate α-Synuclein(α-Syn)-induced neurodegeneration, allowing us to nominate new genes in previously known PD loci. We also uncovered additional novel PD candidate genes within GWAS suggestive loci (e.g. TTC19, ADORA2B, LZTS3, NRBP1, HN1L), which are also supported by clinical and functional evidence. These findings deepen our understanding of PD, and support applying our integrative approach to other complex trait disorders. Ye H, Robak LA, Yu M, Cykowski M, Shulman JM. Genetics and Pathogenesis of Parkinson's Syndrome. https://pubmed.ncbi.nlm.nih.gov/36100231/ Annual Review of Pathology. 2023 Jan 24; 18(1). PDF AbstractParkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops a virtually unique form of Parkinson's syndrome. Clinical manifestations consist of variable motor and nonmotor features, and myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central and peripheral nervous systems, the distribution varies and other pathologies commonly modify PD or trigger similar manifestations. Nearly all PD is genetically influenced. More than 100 genes or genetic loci have been identified, and most cases likely arise from interactions among many common and rare genetic variants. Despite its complex architecture, insights from experimental genetic dissection coalesce to reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms of pathogenesis. This emerging understanding of Parkinson's syndrome, coupled with advances in biomarkers and targeted therapies, presages successful precision medicine strategies. Yu M, Ye H, De-Paula RB, Mangleburg CG, Wu T, Lee TV, Li Y, Duong D, Phillips B, Cruchaga C, Allen GI, Seyfried NT, Al-Ramahi I, Botas J, Shulman JM. Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity. https://pubmed.ncbi.nlm.nih.gov/37200393/ PLoS Genetics. 2023 May 18; 19(5). PDF AbstractHeterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson's disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 86 conserved fly homologs of 37 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, including knockdown of fly homologs of GBA and other LSD genes with independent support as PD susceptibility factors from human genetics (SCARB2, SMPD1, CTSD, GNPTAB, SLC17A5). For several genes, results from multiple alleles suggest dose-sensitivity and context-dependent pleiotropy in the presence or absence of αSyn. Homologs of two genes causing cholesterol storage disorders, Npc1a / NPC1 and Lip4 / LIPA, were independently confirmed as loss-of-function enhancers of αSyn-induced retinal degeneration. The enzymes encoded by several modifier genes are upregulated in αSyn transgenic flies, based on unbiased proteomics, revealing a possible, albeit ineffective, compensatory response. Overall, our results reinforce the important role of lysosomal genes in brain health and PD pathogenesis, and implicate several metabolic pathways, including cholesterol homeostasis, in αSyn-mediated neurotoxicity. Smith HS, Robinson JO, Levchenko A, Pereira S, Pascual B, Bradbury K, Arbones V, Fong J, Shulman JM, McGuire AL, Masdeu J. Research Participants' Perspectives on Precision Diagnostics for Alzheimer's Disease. https://pubmed.ncbi.nlm.nih.gov/38250770/ Journal of Alzheimer's Disease. 2024 Jan 30; 97(3). AbstractBackground: Understanding research participants' responses to learning Alzheimer's disease (AD) risk information is important to inform clinical implementation of precision diagnostics given rapid advances in disease modifying therapies. Objective: We assessed participants' perspectives on the meaning of their amyloid positron emission tomography (PET) imaging results for their health, self-efficacy to understand their results, psychological impact of learning their results, experience receiving their results from the clinical team, and interest in genetic testing for AD risk. Methods: We surveyed individuals who were being clinically evaluated for AD and received PET imaging six weeks after the return of results. We analyzed responses to close-ended survey items by PET result using Fisher's exact test and qualitatively coded open-ended responses. Results: A total of 88 participants completed surveys, most of whom had mild cognitive impairment due to AD (38.6%), AD (28.4%), or were cognitively unimpaired (21.6%). Participants subjectively understood their results (25.3% strongly agreed, 41.8% agreed), which could help them plan (16.5% strongly agreed, 49.4% agreed). Participants with a negative PET result (n = 25) reported feelings of relief (Fisher's exact p < 0.001) and happiness (p < 0.001) more frequently than those with a positive result. Most participants felt that they were treated respectfully and were comfortable voicing concerns during the disclosure process. Genetic testing was anticipated to be useful for medical care decisions (48.2%) and to inform family members about AD risk (42.9%). Conclusions: Participants had high subjective understanding and self-efficacy around their PET results and did not experience negative psychological effects. Interest in genetic testing was high. 2022 
Hill EJ, Robak LA, Al-Ouran R, Deger J, Fong JC, Vandeventer PJ, Schulman E, Rao S, Saade H, Savitt JM, von Coelln R, Desai N, Doddapaneni H, Salvi S, Dugan-Perez S, Muzny DM, McGuire AL, Liu Z, Gibbs RA, Shaw C, Jankovic J, Shulman LM, Shulman JM. Genome Sequencing in the Parkinson Disease Clinic. https://pubmed.ncbi.nlm.nih.gov/35747619/ Neurology Genetics. 2022 Jun 9; 8(4). PDF AbstractBackground and objectives: Genetic variants affect both Parkinson disease (PD) risk and manifestations. Although genetic information is of potential interest to patients and clinicians, genetic testing is rarely performed during routine PD clinical care. The goal of this study was to examine interest in comprehensive genetic testing among patients with PD and document reactions to possible findings from genome sequencing in 2 academic movement disorder clinics. Methods: In 203 subjects with PD (age = 63 years, 67% male), genome sequencing was performed and filtered using a custom panel, including 49 genes associated with PD, parkinsonism, or related disorders, as well as a 90-variant PD genetic risk score. Based on the results, 231 patients (age = 67 years, 63% male) were surveyed on interest in genetic testing and responses to vignettes covering (1) familial risk of PD (LRRK2); (2) risk of PD dementia (GBA); (3) PD genetic risk score; and (4) secondary, medically actionable variants (BRCA1). Results: Genome sequencing revealed a LRRK2 variant in 3% and a GBA risk variant in 10% of our clinical sample. The genetic risk score was normally distributed, identifying 41 subjects with a high risk of PD. Medically actionable findings were discovered in 2 subjects (1%). In our survey, the majority (82%) responded that they would share a LRRK2 variant with relatives. Most registered unchanged or increased interest in testing when confronted with a potential risk for dementia or medically actionable findings, and most (75%) expressed interest in learning their PD genetic risk score. Discussion: Our results highlight broad interest in comprehensive genetic testing among patients with PD and may facilitate integration of genome sequencing in clinical practice. Lagisetty Y, Bourquard T, Al-Ramahi I, Mangleburg CG, Mota S, Soleimani S, Shulman JM, Botas J, Lee K, Lichtarge O. Identification of risk genes for Alzheimer's disease by gene embedding. https://pubmed.ncbi.nlm.nih.gov/36268052/ Cell Genomics. 2022 Sep 14; 2(9). AbstractMost disease-gene association methods do not account for gene-gene interactions, even though these play a crucial role in complex, polygenic diseases like Alzheimer's disease (AD). To discover new genes whose interactions may contribute to pathology, we introduce GeneEMBED. This approach compares the functional perturbations induced in gene interaction network neighborhoods by coding variants from disease versus healthy subjects. In two independent AD cohorts of 5,169 exomes and 969 genomes, GeneEMBED identified novel candidates. These genes were differentially expressed in post mortem AD brains and modulated neurological phenotypes in mice. Four that were differentially overexpressed and modified neurodegeneration in vivo are PLEC, UTRN, TP53, and POLD1. Notably, TP53 and POLD1 are involved in DNA break repair and inhibited by approved drugs. While these data show proof of concept in AD, GeneEMBED is a general approach that should be broadly applicable to identify genes relevant to risk mechanisms and therapy of other complex diseases. Ye F, Funk Q, Rockers E, Shulman JM, Masdeu JC, Pascual B. In Alzheimer-prone brain regions, metabolism and risk-gene expression are strongly correlated. https://pubmed.ncbi.nlm.nih.gov/36092303/ Brain Communications. 2022 Aug 25; 4(5). AbstractNeuroimaging in the preclinical phase of Alzheimer's disease provides information crucial to early intervention, particularly in people with a high genetic risk. Metabolic network modularity, recently applied to the study of dementia, is increased in Alzheimer's disease patients compared with controls, but network modularity in cognitively unimpaired elderly with various risks of developing Alzheimer's disease needs to be determined. Based on their 5-year cognitive progression, we stratified 117 cognitively normal participants (78.3 ± 4.0 years of age, 52 women) into three age-matched groups, each with a different level of risk for Alzheimer's disease. From their fluorodeoxyglucose PET we constructed metabolic networks, evaluated their modular structures using the Louvain algorithm, and compared them between risk groups. As the risk for Alzheimer's disease increased, the metabolic connections among brain regions weakened and became more modular, indicating network fragmentation and functional impairment of the brain. We then set out to determine the correlation between regional brain metabolism, particularly in the modules derived from the previous analysis, and the regional expression of Alzheimer-risk genes in the brain, obtained from the Allen Human Brain Atlas. In all risk groups of this elderly population, the regional brain expression of most Alzheimer-risk genes showed a strong correlation with brain metabolism, particularly in the module that corresponded to regions of the brain that are affected earliest and most severely in Alzheimer's disease. Among the genes, APOE and CD33 showed the strongest negative correlation and SORL1 showed the strongest positive correlation with brain metabolism. The Pearson correlation coefficients remained significant when contrasted against a null-hypothesis distribution of correlation coefficients across the whole transcriptome of 20 736 genes (SORL1: P = 0.0130; CD33, P = 0.0136; APOE: P = 0.0093). The strong regional correlation between Alzheimer-related gene expression in the brain and brain metabolism in older adults highlights the role of brain metabolism in the genesis of dementia. 2021 Dunham-Alfradique I, Al-Ouran R, von Coelln R, Blauwendraat C, Hill EJ, Luo L, Stillwell A, Young E, Tan M, Liao C, Hernandez D, Pihlstrom L, Grosset D, Shulman LM, Liu Z, Rouleau G, International Parkinson's Disease Genomics Consortium, Nalls M, Singleton A, Morris H, Jankovic J, Shulman JM. Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes. https://pubmed.ncbi.nlm.nih.gov/33987465/ Neurology Genetics. 2021 Jan 28; 7(2). PDF ABSTRACT
Objective: To discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms.
Methods: In 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at onset, disease duration, and 5 ancestry principal components, followed by meta-analysis. Results: Among 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199351, p subtype = 0.01, p ratio = 0.03), SH3GL2 (rs10756907, p subtype = 0.02, p ratio = 0.01), HIP1R (rs10847864, p subtype = 0.02), RIT2 (rs12456492, p subtype = 0.02), and FBRSL1 (rs11610045, p subtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = -0.04, 95% confidence interval = -0.07-0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, p ratio = 6.6 × 10-7), which harbors an independent risk allele for essential tremor. Conclusions: Multiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD. 
Hill EJ, Mangleburg CG, Dunham-Alfradique I, Ripperger B, Stillwell A, Rao S, Saade H, Fagbongbe F, von Coelln R, Jankovic J, Dawe R, Shulman LM, Buchman A, Shulman JM. Quantitative mobility measures complement the MDS-UPDRS for characterization of Parkinson's disease heterogeneity. https://pubmed.ncbi.nlm.nih.gov/33607526/ Parkinsonism & Related Disorders. 2021 Mar; 84. PDF ABSTRACT
Introduction: Emerging technologies show promise for enhanced characterization of Parkinson's Disease (PD) motor manifestations. We evaluated quantitative mobility measures from a wearable device compared to the conventional motor assessment, the Movement Disorders Society-Unified PD Rating Scale part III (motor MDS-UPDRS).
Methods: We evaluated 176 PD subjects (mean age 65, 65% male, 66% H&Y stage 2) during routine clinic visits using the motor MDS-UPDRS and a 10-min motor protocol with a body-fixed sensor (DynaPort MT, McRoberts BV), including the 32-ft walk, Timed Up and Go (TUG), and standing posture with eyes closed. Regression models examined 12 quantitative mobility measures for associations with (i) motor MDS-UPDRS, (ii) motor subtype (tremor dominant vs. postural instability/gait difficulty), (iii) Montreal Cognitive Assessment (MoCA), and (iv) physical functioning disability (PROMIS-29). All analyses included age, gender, and disease duration as covariates. Models iii-iv were secondarily adjusted for motor MDS-UPDRS. Results: Quantitative mobility measures from gait, TUG transitions, turning, and posture were significantly associated with motor MDS-UPDRS (7 of 12 measures, p < 0.05) and motor subtype (6 of 12 measures, p < 0.05). Compared with motor MDS-UPDRS, several quantitative mobility measures accounted for a 1.5- or 1.9-fold increased variance in either cognition or physical functioning disability, respectively. Among minimally-impaired subjects in the bottom quartile of motor MDS-UPDRS, including subjects with normal gait exam, the measures captured substantial residual motor heterogeneity. Conclusion: Clinic-based quantitative mobility assessments using a wearable sensor captured features of motor performance beyond those obtained with the motor MDS-UPDRS and may offer enhanced characterization of disease heterogeneity. Guo Q, Dammer EB, Zhou M, Kundinger SR, Gearing M, Lah JJ, Levey AI, Shulman JM, Seyfried NT. Targeted quantification of detergent-insoluble RNA-binding proteins in human brain reveals stage and disease-specific co-aggregation in Alzheimer's disease. https://pubmed.ncbi.nlm.nih.gov/33815056/ Frontiers in Molecular Neuroscience. 2021 Mar 18; 14. PDF ABSTRACT
Core spliceosome and related RNA-binding proteins aggregate in Alzheimer's disease (AD) brain even in early asymptomatic stages (AsymAD) of disease. To assess the specificity of RNA-binding protein aggregation in AD, we developed a targeted mass spectrometry approach to quantify broad classes of RNA-binding proteins with other pathological proteins including tau and amyloid beta (Aβ) in detergent insoluble fractions from control, AsymAD, AD and Parkinson's disease (PD) brain. Relative levels of specific insoluble RNA-binding proteins across different disease groups correlated with accumulation of Aβ and tau aggregates. RNA-binding proteins, including splicing factors with homology to the basic-acidic dipeptide repeats of U1-70K, preferentially aggregated in AsymAD and AD. In contrast, PD brain aggregates were relatively depleted of many RNA-binding proteins compared to AsymAD and AD groups. Correlation network analyses resolved 29 distinct modules of co-aggregating proteins including modules linked to spliceosome assembly, nuclear speckles and RNA splicing. Modules related to spliceosome assembly and nuclear speckles showed stage-specific enrichment of insoluble RBPs from AsymAD and AD brains, whereas the RNA splicing module was reduced specifically in PD. Collectively, this work identifies classes of RNA-binding proteins that distinctly co-aggregate in detergent-insoluble fractions across the specific neurodegenerative diseases we examined.
Bailey M, Shulman LM, Ryan D, Ouyang B, Shulman JM, Buchman AS, Bennett DA, Barnes LL, Hall DA. Frequency of Parkinsonism and Parkinson Disease in African Americans in Community and Clinic Settings in Chicago. https://pubmed.ncbi.nlm.nih.gov/33631006/ J Gerontol A. 2021 Jun 14; 76(7). ABSTRACT
Background: There is paucity of data about African American (AA) patients with Parkinson's disease (PD) and parkinsonism which may precede PD in older adults. Prior studies suggest that there are lower rates of PD in the AA population, with more cognitive impairment in AA with PD. This study aimed to investigate differences in PD, parkinsonism, and cognition between White and AA populations in 3 longitudinal epidemiologic cohort studies of aging.
Methods: This study examined parkinsonism, PD frequency, and cognition of community-dwelling older individuals in 3 longitudinal epidemiologic cohort studies. Parkinsonism was based on an exam utilizing the modified Unified Parkinson's Disease Rating Scale performed by a nurse. PD was based on self-report, medications used for treatment of PD, and examination findings. Cognition was assessed using 19 performance-based tests that assess 5 cognitive domains. Results: AA participants were less likely to have parkinsonism compared to Whites, even with age and gender differences. Frequency of PD was not significant between groups. AA were more likely to have lower cognitive scores as compared to Whites. AA were less likely to have parkinsonism even with controlling for cognitive differences between groups. Conclusions: Parkinsonian signs are present among AA in the community at lower rates than in White individuals. Cognitive profiles of AA and Whites with parkinsonism may be different, suggesting differing contributions of pathology to cognitive decline and parkinsonism between groups. Additional research is needed to understand the progression of parkinsonism to PD, as well as to understanding the cognitive differences in AA with parkinsonism. Abreha MH, Ojelade S, Dammer EB, McEachin ZT, Duong DM, Gearing M, Bassell GJ, Lah JJ, Levey AI, Shulman JM*, Seyfried NT*. TBK1 Interacts with Tau and Enhances Neurodegeneration in Tauopathy. https://pubmed.ncbi.nlm.nih.gov/33965374/ Journal of Biological Chemistry. 2021 Jan-Jun; 296. *Co-senior and Co-corresponding authors. PDF ABSTRACT
One of the defining pathological features of Alzheimer's disease (AD) is the deposition of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau in the brain. Aberrant activation of kinases in AD has been suggested to enhance phosphorylation and toxicity of tau, making the responsible tau kinases attractive therapeutic targets. The full complement of tau-interacting kinases in AD brain and their activity in disease remains incompletely defined. Here, immunoaffinity enrichment coupled with mass spectrometry (MS) identified TANK-binding kinase 1 (TBK1) as a tau-interacting partner in human AD cortical brain tissues. We validated this interaction in human AD, familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in MAPT (R406W & P301L) and corticobasal degeneration (CBD) postmortem brain tissues as well as human cell lines. Further, we document increased TBK1 activation in both AD and FTDP-17 and map TBK1 phosphorylation sites on tau based on in vitro kinase assays coupled to MS. Lastly, in a Drosophila tauopathy model, activating expression of a conserved TBK1 ortholog triggers tau hyperphosphorylation and enhanced neurodegeneration, whereas knockdown had the reciprocal effect, suppressing tau toxicity. Collectively, our findings suggest that increased TBK1 activation may promote tau hyperphosphorylation and neuronal loss in AD and related tauopathies.
Petyuk VA, Yu L, Olson HM, Yu F, Clair G, Qian W-J, Shulman JM, Bennett DA. Proteomic Profiling of the Substantia Nigra to Identify Determinants of Lewy Body Pathology and Dopaminergic Neuronal Loss. https://pubmed.ncbi.nlm.nih.gov/33900085/ Journal of Proteome Research. 2021 May 7; 20(5). PDF ABSTRACT
Proteinaceous aggregates containing α-synuclein protein called Lewy bodies in the substantia nigra is a hallmark of Parkinson's disease. The molecular mechanisms of Lewy body formation and associated neuronal loss remain largely unknown. To gain insights into proteins and pathways associated with Lewy body pathology, we performed quantitative profiling of the proteome. We analyzed substantia nigra tissue from 51 subjects arranged into three groups: cases with Lewy body pathology, Lewy body-negative controls with matching neuronal loss, and controls with no neuronal loss. Using a label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach, we characterized the proteome both in terms of protein abundances and peptide modifications. Statistical testing for differential abundance of the most abundant 2963 proteins, followed by pathway enrichment and Bayesian learning of the causal network structure, was performed to identify likely drivers of Lewy body formation and dopaminergic neuronal loss. The identified pathways include (1) Arp2/3 complex-mediated actin nucleation; (2) synaptic function; (3) poly(A) RNA binding; (4) basement membrane and endothelium; and (5) hydrogen peroxide metabolic process. According to the data, the endothelial/basement membrane pathway is tightly connected with both pathologies and likely to be one of the drivers of neuronal loss. The poly(A) RNA-binding proteins, including the ones relevant to other neurodegenerative disorders (e.g., TDP-43 and FUS), have a strong inverse correlation with Lewy bodies and may reflect an alternative mechanism of nigral neurodegeneration.
2020 
Yao T, Nagorski J, Sweeney E, Shulman JM, Allen G. Quantifying Cognitive Resilience in Alzheimer's Disease: The Alzheimer's Disease Cognitive Resilience Score. https://pmc.ncbi.nlm.nih.gov/articles/PMC7643963/ PLoS One. 2020 Nov 5; 15(11). ABSTRACT
Even though there is a clear link between Alzheimer’s Disease (AD) related neuropathology and cognitive decline, numerous studies have observed that healthy cognition can exist in the presence of extensive AD pathology, a phenomenon sometimes called Cognitive Resilience (CR). To better understand and study CR, we develop the Alzheimer’s Disease Cognitive Resilience Score (AD-CR Score), which we define as the difference between the observed and expected cognition given the observed level of AD pathology. Unlike other definitions of CR, our AD-CR Score is a fully non-parametric, stand-alone, individual-level quantification of CR that is derived independently of other factors or proxy variables. Using data from two ongoing, longitudinal cohort studies of aging, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP), we validate our AD-CR Score by showing strong associations with known factors related to CR such as baseline and longitudinal cognition, non AD-related pathology, education, personality, APOE, parkinsonism, depression, and life activities. Even though the proposed AD-CR Score cannot be directly calculated during an individual’s lifetime because it uses postmortem pathology, we also develop a machine learning framework that achieves promising results in terms of predicting whether an individual will have an extremely high or low AD-CR Score using only measures available during the lifetime. Given this, our AD-CR Score can be used for further investigations into mechanisms of CR, and potentially for subject stratification prior to clinical trials of personalized therapies.
Mangleburg CG, Wu T, Yalamanchili H, Guo C, Dammer E, Hsieh Y-C, De Jager P, Levey A, Seyfried N, Liu Z, Shulman JM. Integrated analysis of the aging brain transcriptome and proteome in tauopathy. https://pubmed.ncbi.nlm.nih.gov/32993812/ Molecular Neurodegeneration. 2020 Sep 29; 15(1). ABSTRACT
Background: Tau neurofibrillary tangle pathology characterizes Alzheimer's disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes.
Methods: Paired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (TauWT) or a mutant form causing frontotemporal dementia (TauR406W). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy. Results: TauWT induced 1514 and 213 differentially expressed transcripts and proteins, respectively. TauR406W had a substantially greater impact, causing changes in 5494 transcripts and 697 proteins. There was a ~ 70% overlap between age- and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes. Conclusions: Our results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome. Wan Y-W, Al-Ouran R, Mangleburg CG, Perumal TM, Lee TV, Allison K, Swarup V, Funk CC, Gaiteri C, Allen M, Wang M, Bendl J, Chibnik LB, Bennett DA, De Jager PL, Zhang B, Mangravite LM, Logsdon BA, Liu Z, Shulman JM; Accelerating Medicines Partnership-Alzheimer's Disease Consortium. Meta-analysis of the Alzheimer's disease brain transcriptome and functional dissection in mouse models. https://pubmed.ncbi.nlm.nih.gov/32668255/ Cell Reports. 2020 Jul 14; 32(2). ABSTRACT
We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.
Robak LA, Du R, Yuan B, Gu S, Alfradique-Dunham I, Kondapali V, Hinojosa E, Stillwell A, Young E, Zhang C, Song X, Du H, Gambin T, Jhangiani SN, Akdemir ZC, Muzny DM, Tejomurtula A, Ross OA, Shaw C, Jankovic J, Bi W, Posey J, Lupski JR, Shulman JM. Integrated Exome Sequencing and Array Comparative Genomic Hybridization in Familial Parkinson's Disease. https://pubmed.ncbi.nlm.nih.gov/32802956/ Neurology Genetics. 2020 Jul 28; 6(5). ABSTRACT
Objective: To determine how single nucleotide variants (SNVs) and copy number variants (CNVs) contribute to molecular diagnosis in familial Parkinson disease (PD), we integrated exome sequencing (ES) and genome-wide array-based comparative genomic hybridization (aCGH) and further probed CNV structure to reveal mutational mechanisms.
Methods: We performed ES on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated ES and aCGH data for pathogenic SNVs and CNVs at Mendelian PD gene loci. We confirmed SNVs via Sanger sequencing and further characterized CNVs with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing. Results: Using ES, we discovered individuals with known pathogenic SNVs in GBA (p.Glu365Lys, p.Thr408Met, p.Asn409Ser, and p.Leu483Pro) and LRRK2 (p.Arg1441Gly and p.Gly2019Ser). Two subjects were each double heterozygotes for variants in GBA and LRRK2. Based on aCGH, we additionally discovered cases with an SNCA duplication and heterozygous intragenic GBA deletion. Five additional subjects harbored both SNVs (p.Asn52Metfs*29, p.Thr240Met, p.Pro437Leu, and p.Trp453*) and likely disrupting CNVs at the PRKN locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors. Conclusions: Integrated ES and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PRKN CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles. Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, Higginbotham LA, Guajardo A, White B, Troncoso JC, Thambisetty M, Montine TJ, Lee EB, Trojanowski JQ, Beach TG, Reiman EM, Haroutunian V, Wang M, Schadt E, Zhang B, Dickson DW, Ertekin-Taner N, Golde TE, Petyuk VA, De Jager PL, Bennett DA, Wingo TS, Rangaraju S, Hajjar I, Shulman JM, Lah JJ, Levey AI, Seyfried NT. Large-scale Proteomic Analysis of Alzheimer's Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation. https://pubmed.ncbi.nlm.nih.gov/32284590/ Nature Medicine. 2020 May; 26(5). ABSTRACT
Our understanding of Alzheimer's disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.
Ye H, Ojelade S, Li-Kroeger D, Zuo Z, Duraine L, He Y, Li Y, Tepass U, Rodal A, Wang L, Bellen HJ, Shulman JM. The retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain. https://pubmed.ncbi.nlm.nih.gov/32286230/ eLife. 2020 Apr 14; 9. https://elifesciences.org/articles/51977 ABSTRACT
Retromer, including Vps35, Vps26, and Vps29, is a protein complex responsible for recycling proteins within the endolysosomal pathway. Although implicated in both Parkinson's and Alzheimer's disease, our understanding of retromer function in the adult brain remains limited, in part because Vps35 and Vps26 are essential for development. In Drosophila, we find that Vps29 is dispensable for embryogenesis but required for retromer function in aging adults, including for synaptic transmission, survival, and locomotion. Unexpectedly, in Vps29 mutants, Vps35 and Vps26 proteins are normally expressed and associated, but retromer is mislocalized from neuropil to soma with the Rab7 GTPase. Further, Vps29 phenotypes are suppressed by reducing Rab7 or overexpressing the GTPase activating protein, TBC1D5. With aging, retromer insufficiency triggers progressive endolysosomal dysfunction, with ultrastructural evidence of impaired substrate clearance and lysosomal stress. Our results reveal the role of Vps29 in retromer localization and function, highlighting requirements for brain homeostasis in aging.
Blauwendraat C, Reed X, Krohn L, Heilbron K, Bandres-Ciga S, Tan M, Gibbs JR, Hernandez DG, Kumaran R, Langston JW, Bonet-Ponce L, Alcalay RN, Hassin-Baer S, Greenbaum L, Iwaki H, Leonard HL, Liu G, Maple-Grødem J, Saunders-Pullman R, Mickel SF, Schulz J, Wolff R, Singleton AB, Nalls MA, Gan-Or Z, Cookson MR, Morris HR, Jankovic J, Shulman LM, Shulman JM. Genetic modifiers of risk and age of onset in GBA associated Parkinson's disease and Lewy body dementia. https://pubmed.ncbi.nlm.nih.gov/31755958/ Brain. 2020 Jan 1; 143(1). ABSTRACT
Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.
2019 
Hsieh Y-C, Guo C, Yalamanchili HK, Abreha M, Al-Ouran R, Li Y, Dammer E, Lah JJ, Levey AI, Bennett DA, De Jager PL, Seyfried NT, Liu Z, Shulman JM. Tau-mediated disruption of the spliceosome triggers cryptic RNA splicing and neurodegeneration in Alzheimer's disease. https://pubmed.ncbi.nlm.nih.gov/31597093/ Cell Reports. 2019 Oct 8; 29(2). ABSTRACT
In Alzheimer's disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal components. In Drosophila, pan-neuronal Tau expression triggers reductions in multiple core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss of function in SmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA sequencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle burden. Our results implicate spliceosome disruption and the resulting transcriptome perturbation in Tau-mediated neurodegeneration in AD.
Ojelade S, Lee T, Giagtzoglou N, Yu L, Ugur B, Duraine L, Zuo Z, Petyuk V, De Jager PL, Bennett DA, Arenkiel BR, Bellen HJ, Shulman JM. Cindr, the Drosophila homolog of the Alzheimer's disease risk gene, is required for synaptic transmission and proteostasis. https://pubmed.ncbi.nlm.nih.gov/31412248/ Cell Reports. 2019 Aug 13; 28(7). ABSTRACT
The Alzheimer's disease (AD) susceptibility gene, CD2-associated protein (CD2AP), encodes an actin binding adaptor protein, but its function in the nervous system is largely unknown. Loss of the Drosophila ortholog cindr enhances neurotoxicity of human Tau, which forms neurofibrillary tangle pathology in AD. We show that Cindr is expressed in neurons and present at synaptic terminals. cindr mutants show impairments in synapse maturation and both synaptic vesicle recycling and release. Cindr associates and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and the plasma membrane calcium ATPase (PMCA). Loss of cindr elevates PMCA levels and reduces cytosolic calcium. Studies of Cd2ap null mice support a conserved role in synaptic proteostasis, and CD2AP protein levels are inversely related to Synapsin abundance in human postmortem brains. Our results reveal CD2AP neuronal requirements with relevance to AD susceptibility, including for proteostasis, calcium handling, and synaptic structure and function.
von Coelln R, Dawe RJ, Leurgans SE, Curran TA, Truty T, Yu L, Barnes LL, Shulman JM, Shulman LM, Bennett DA, Hausdorff JM, Buchman AS. Quantitative mobility metrics derived from a wearable sensor predict incident parkinsonism in older adults. https://pubmed.ncbi.nlm.nih.gov/31272924/ Parkinsonism & Related Disorders. 2019 Aug; 65. ABSTRACT
Introduction: Mobility metrics derived from wearable sensor recordings are associated with parkinsonism in older adults. We examined if these metrics predict incident parkinsonism.
Methods: Parkinsonism was assessed annually in 683 ambulatory, community-dwelling older adults without parkinsonism at baseline. Four parkinsonian signs were derived from a modified Unified Parkinson's Disease Rating Scale (UPDRS). Parkinsonism was based on the presence of 2 or more signs. Participants wore a sensor on their back while performing a 32 foot walk, standing posture, and Timed Up and Go (TUG) tasks. 12 mobility scores were extracted. Cox proportional hazards models with backward elimination were used to identify combinations of mobility scores independently associated with incident parkinsonism. Results: During follow-up of 2.5 years (SD = 1.28), 139 individuals developed parkinsonism (20.4%). In separate models, 6 of 12 mobility scores were individually associated with incident parkinsonism, including: Speed and Regularity (from 32 ft walk), Sway (from standing posture), and 3 scores from TUG subtasks (Posterior sit to stand transition, Range stand to sit transition, and Yaw, a measure of turning efficiency). When all mobility scores were analyzed together in a single model, 2 TUG subtask scores, Range from stand to sit transition (HR, 1.42, 95%CI, 1.09, 1.82) and Yaw from turning (HR, 0.56, 95%CI, 0.42, 0.73) were independently associated with incident parkinsonism. These results were unchanged when controlling for chronic health covariates. Conclusion: Mobility metrics derived from a wearable sensor complement conventional gait testing and have potential to enhance risk stratification of older adults who may develop parkinsonism. Ysselstein D, Shulman JM, Krainc D. Emerging Links Between Pediatric Lysosomal Storage Diseases and Adult Movement Disorders. https://pmc.ncbi.nlm.nih.gov/articles/PMC6520126/ Movement Disorders. 2019 May; 34(5). ABSTRACT
Lysosomal storage disorders (LSDs) comprise a clinically heterogeneous group of autosomal recessive or X-linked genetic syndromes caused by disruption of lysosomal biogenesis or function resulting in the accumulation of non-degraded substrates. Although LSDs are diagnosed predominantly in children, many show variable expressivity with clinical presentations possible later in life. Given the important role of lysosomes in neuronal homeostasis, neurologic manifestations, including movement disorders, can accompany many LSDs. Over the last decade, evidence from genetics, clinical epidemiology, cell biology, and biochemistry have converged to implicate links between LSDs and adult-onset movement disorders. The strongest evidence comes from mutations in Glucocerebrosidase, which cause Gaucher disease (GD), and are among the most common and potent risk factors for Parkinson’s disease (PD). However, recently many additional LSD genes have been similarly implicated, including SMPD1, ATP13A2, GALC, and others. Examination of these links can offer insight into pathogenesis of Parkinson’s disease and guide development of new therapeutic strategies. We systematically review the emerging genetic links between LSDs and PD.
Blauwendraat C, Heilbron K, Vallerga CL, Bandres-Ciga S, von Coelln R, Pihlstrom L, Simon-Sanchez J, Schulte C, Sharma M, Krohn L, Siitonen A, Iwaki H, Leonard H, Noyce AJ, Tan M, Gibbs JR, Hernandez DG, Scholz SW, Jankovic J, Shulman LM, Lesage S, Corvol JC, Brice A, van Hilten JJ, Marinus J; 23andMe Research Team, Eerola-Rautio J, Tienari P, Majamaa K, Toft M, Grosset DG, Gasser T, Heutink P, Shulman JM, Wood N, Hardy J, Morris HR, Hinds DA, Gratten J, Visscher PM, Gan-Or Z, Nalls MA, Singleton AB; International Parkinson's Disease Genomics Consortium. Parkinson's disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms. https://pubmed.ncbi.nlm.nih.gov/30957308/ Movement Disorders. 2019 Jun; 34(6). ABSTRACTBackground: Objectives: Methods: Results: Conclusions: Buchman AS, Yu L, Wilson RS, Leurgans SE, Nag S, Shulman JM, Barnes LL, Schneider JA, Bennett DA. Progressive parkinsonism in older adults is related to the burden of mixed-brain pathologies. https://pubmed.ncbi.nlm.nih.gov/30894446/ Neurology. 2019 Apr 16; 92(16). ABSTRACTObjective: Methods: Results: Conclusion: 2018 
Rousseaux MW, Vazquez-Velez GE, Al-Ramahi I, Jeong H-H, Bajic A, Revelli J-P, Ye H, Phan E, Deger J, Perez A, Kim J-Y, Lavery L, Xu Q, Li M, Kang H, Shulman JM, Westbrook TF, Elledge SJ, Liu Z, Botas J, Zoghbi HY. A druggable genome screen identifies modifiers of α-synuclein levels via a tiered cross-species validation approach. https://pubmed.ncbi.nlm.nih.gov/30249792/ Journal of Neuroscience. 2018 Oct 24; 38(43). ABSTRACT
Accumulation of α-Synuclein (α-Syn) causes Parkinson's disease (PD) as well as other synucleopathies. α-Syn is the major component of Lewy bodies and Lewy neurites, the proteinaceous aggregates that are a hallmark of sporadic PD. In familial forms of PD, mutations or copy number variations in SNCA (the α-Syn gene) result in a net increase of its protein levels. Furthermore, common risk variants tied to PD are associated with small increases of wild-type α-Syn levels. These findings are further bolstered by animal studies which show that overexpression of α-Syn is sufficient to cause PD-like features. Thus, increased α-Syn levels are intrinsically tied to PD pathogenesis and underscore the importance of identifying the factors that regulate its levels. In this study, we establish a pooled RNAi screening approach and validation pipeline to probe the druggable genome for modifiers of α-Syn levels and identify 60 promising targets. Using a cross-species, tiered validation approach, we validate six strong candidates that modulate α-Syn levels and toxicity in cell lines, Drosophila, human neurons, and mouse brain of both sexes. More broadly, this genetic strategy and validation pipeline can be applied for the identification of therapeutic targets for disorders driven by dosage-sensitive proteins.
Guo C, Hwang J, Hsieh Y-C, Klein H-U, Bennett DA, De Jager PL, Liu Z, Shulman JM. Tau Activates Transposable Elements in Alzheimer's disease. https://pubmed.ncbi.nlm.nih.gov/29874575/ Cell Reports. 2018 Jun 5; 23(10). ABSTRACT
Aging and neurodegenerative disease are characterized by genomic instability in neurons, including aberrant activation and mobilization of transposable elements (TEs). Integrating studies of human postmortem brain tissue and Drosophila melanogaster models, we investigate TE activation in association with Tau pathology in Alzheimer's disease (AD). Leveraging RNA sequencing from 636 human brains, we discover differential expression for several retrotransposons in association with neurofibrillary tangle burden and highlight evidence for global TE transcriptional activation among the long interspersed nuclear element 1 and endogenous retrovirus clades. In addition, we detect Tau-associated, active chromatin signatures at multiple HERV-Fc1 genomic loci. To determine whether Tau is sufficient to induce TE activation, we profile retrotransposons in Drosophila expressing human wild-type or mutant Tau throughout the brain. We discover heterogeneous response profiles, including both age- and genotype-dependent activation of TE expression by Tau. Our results implicate TE activation and associated genomic instability in Tau-mediated AD mechanisms.
Jeong H-H, Yalamanchili HK, Guo C, Shulman JM, Liu Z. An Ultra-Fast and Scalable Quantification Pipeline for Transposable Elements from Next Generation Sequencing Data. https://pubmed.ncbi.nlm.nih.gov/29218879/ Pac Symp Biocomputing. 2018; 23. ABSTRACT
Transposable elements (TEs) are DNA sequences which are capable of moving from one location to another and represent a large proportion (45%) of the human genome. TEs have functional roles in a variety of biological phenomena such as cancer, neurodegenerative disease, and aging. Rapid development in RNA-sequencing technology has enabled us, for the first time, to study the activity of TE at the systems level. However, efficient TE analysis tools are not yet developed. In this work, we developed SalmonTE, a fast and reliable pipeline for the quantification of TEs from RNA-seq data. We benchmarked our tool against TEtranscripts, a widely used TE quantification method, and three other quantification methods using several RNA-seq datasets from Drosophila melanogaster and human cell-line. We achieved 20 times faster execution speed without compromising the accuracy. This pipeline will enable the biomedical research community to quantify and analyze TEs from large amounts of data and lead to novel TE centric discoveries.
2017 Robak LA, Jansen IE, van Rooij J, Uitterlinden AG, Kraaij R, Jankovic J; International Parkinson’s Disease Genomics Consortium (IPDGC); Heutink P, Shulman JM. Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. https://pubmed.ncbi.nlm.nih.gov/29140481/ Brain. 2017 Dec 1; 140(12). ABSTRACT
Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility.
Wangler MF, Hu Y, Shulman JM. Drosophila and genome-wide association studies: a review and resource for the functional dissection of human complex traits. https://pubmed.ncbi.nlm.nih.gov/28151408/ Dis Model Mech. 2017 Feb 1; 10(2). ABSTRACT
Human genome-wide association studies (GWAS) have successfully identified thousands of susceptibility loci for common diseases with complex genetic etiologies. Although the susceptibility variants identified by GWAS usually have only modest effects on individual disease risk, they contribute to a substantial burden of trait variation in the overall population. GWAS also offer valuable clues to disease mechanisms that have long proven to be elusive. These insights could lead the way to breakthrough treatments; however, several challenges hinder progress, making innovative approaches to accelerate the follow-up of results from GWAS an urgent priority. Here, we discuss the largely untapped potential of the fruit fly, Drosophila melanogaster, for functional investigation of findings from human GWAS. We highlight selected examples where strong genomic conservation with humans along with the rapid and powerful genetic tools available for flies have already facilitated fine mapping of association signals, elucidated gene mechanisms, and revealed novel disease-relevant biology. We emphasize current research opportunities in this rapidly advancing field, and present bioinformatic analyses that systematically explore the applicability of Drosophila for interrogation of susceptibility signals implicated in more than 1000 human traits, based on all GWAS completed to date. Thus, our discussion is targeted at both human geneticists seeking innovative strategies for experimental validation of findings from GWAS, as well as the Drosophila research community, by whom ongoing investigations of the implicated genes will powerfully inform our understanding of human disease.
Chibnik LB, White CC, Mukherjee S, Raj T, Yu L, Larson EB, Montine TJ, Keene CD, Sonnen J, Schneider JA, Crane PK, Shulman JM, Bennett DA, De Jager PL. Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies. https://pubmed.ncbi.nlm.nih.gov/28322283/ Mol Psychiatry. 2018 Jun; 23(6). ABSTRACT
Tauopathies, including Alzheimer's disease (AD) and other neurodegenerative conditions, are defined by a pathological hallmark: neurofibrillary tangles (NFTs). NFT accumulation is thought to be closely linked to cognitive decline in AD. Here, we perform a genome-wide association study for NFT pathologic burden and report the association of the PTPRD locus (rs560380, P=3.8 × 10-8) in 909 prospective autopsies. The association is replicated in an independent data set of 369 autopsies. The association of PTPRD with NFT is not dependent on the accumulation of amyloid pathology. In contrast, we found that the ZCWPW1 AD susceptibility variant influences NFT accumulation and that this effect is mediated by an accumulation of amyloid β plaques. We also performed complementary analyses to identify common pathways that influence multiple neuropathologies that coexist with NFT and found suggestive evidence that certain loci may influence multiple different neuropathological traits, including tau, amyloid β plaques, vascular injury and Lewy bodies. Overall, these analyses offer an evaluation of genetic susceptibility to NFT, a common end point for multiple different pathologic processes.
Blauwendraat C, Faghri F, Pihlstrom L, Geiger JT, Elbaz A, Lesage S, Corvol JC, May P, Nicolas A, Abramzon Y, Murphy NA, Gibbs JR, Ryten M, Ferrari R, Bras J, Guerreiro R, Williams J, Sims R, Lubbe S, Hernandez DG, Mok KY, Robak L, Campbell RH, Rogaeva E, Traynor BJ, Chia R, Chung SJ; International Parkinson's Disease Genomics Consortium (IPDGC), COURAGE-PD Consortium; Hardy JA, Brice A, Wood NW, Houlden H, Shulman JM, Morris HR, Gasser T, Krüger R, Heutink P, Sharma M, Simón-Sánchez J, Nalls MA, Singleton AB, Scholz SW. NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases. https://pubmed.ncbi.nlm.nih.gov/28602509/ Neurobiol Aging. 2017 Sep; 57. ABSTRACT
Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low-cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases.
Rousseaux MWC, Shulman JM, Jankovic J. Progress toward an integrated understanding of Parkinson's disease. https://pubmed.ncbi.nlm.nih.gov/28751973/ F1000Res. 2017 Jul 12; 6. ABSTRACT
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting over 10 million individuals worldwide. While numerous effective symptomatic treatments are currently available, no curative or disease-modifying therapies exist. An integrated, comprehensive understanding of PD pathogenic mechanisms will likely address this unmet clinical need. Here, we highlight recent progress in PD research with an emphasis on promising translational findings, including (i) advances in our understanding of disease susceptibility, (ii) improved knowledge of cellular dysfunction, and (iii) insights into mechanisms of spread and propagation of PD pathology. We emphasize connections between these previously disparate strands of PD research and the development of an emerging systems-level understanding that will enable the next generation of PD therapeutics.
Jansen IE, Ye H, Heetveld S, Lechler MC, Michels H, Seinstra RI, Lubbe SJ, Drouet V, Lesage S, Majounie E, Gibbs JR, Nalls MA, Ryten M, Botia JA, Vandrovcova J, Simon-Sanchez J, Castillo-Lizardo M, Rizzu P, Blauwendraat C, Chouhan AK, Li Y, Yogi P, Amin N, van Duijn CM; International Parkinson’s Disease Genetics Consortium (IPGDC); Morris HR, Brice A, Singleton AB, David DC, Nollen EA, Jain S, Shulman JM, Heutink P. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. https://pubmed.ncbi.nlm.nih.gov/28137300/ Genome Biol. 2017 Jan 30; 18(1). ABSTRACT
Background: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models.
Results: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. Conclusions: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies. 2016 
Müller SH, Girard SL, Hopfner F, Merner ND, Bourassa CV, Lorenz D, Clark LN, Tittmann L, Soto-Ortolaza AI, Klebe S, Hallett M, Schneider SA, Hodgkinson CA, Lieb W, Wszolek ZK, Pendziwiat M, Lorenzo-Betancor O, Poewe W, Ortega-Cubero S, Seppi K, Rajput A, Hussl A, Rajput AH, Berg D, Dion PA, Wurster I, Shulman JM, Srulijes K, Haubenberger D, Pastor P, Vilariño-Güell C, Postuma RB, Bernard G, Ladwig KH, Dupré N, Jankovic J, Strauch K, Panisset M, Winkelmann J, Testa CM, Reischl E, Zeuner KE, Ross OA, Arzberger T, Chouinard S, Deuschl G, Louis ED, Kuhlenbäumer G, Rouleau GA. Genome-wide association study in essential tremor identifies three new loci. https://pubmed.ncbi.nlm.nih.gov/27797806/ Brain. 2016 Dec 1; 139(12). ABSTRACT
We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
Jakobsdottir J, van der Lee SJ, Bis JC, Chouraki V, Li-Kroeger D, Yamamoto S, Grove ML, Naj A, Vronskaya M, Salazar JL, DeStefano AL, Brody JA, Smith AV, Amin N, Sims R, Ibrahim-Verbaas CA, Choi SH, Satizabal CL, Lopez OL, Beiser A, Ikram MA, Garcia ME, Hayward C, Varga TV, Ripatti S, Franks PW, Hallmans G, Rolandsson O, Jansson JH, Porteous DJ, Salomaa V, Eiriksdottir G, Rice KM, Bellen HJ, Levy D, Uitterlinden AG, Emilsson V, Rotter JI, Aspelund T; Cohorts for Heart and Aging Research in Genomic Epidemiology consortium; Alzheimer’s Disease Genetic Consortium; Genetic and Environmental Risk in Alzheimer’s Disease consortium; O'Donnell CJ, Fitzpatrick AL, Launer LJ, Hofman A, Wang LS, Williams J, Schellenberg GD, Boerwinkle E, Psaty BM, Seshadri S, Shulman JM, Gudnason V, van Duijn CM. Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. https://pubmed.ncbi.nlm.nih.gov/27764101/ PLoS Genetics. 2016 Oct 20; 12(10). ABSTRACT
We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.
Hales CM, Dammer EB, Deng Q, Duong DM, Gearing M, Troncoso JC, Thambisetty M, Lah JJ, Shulman JM, Levey AI, Seyfried NT. Changes in the detergent-insoluble brain proteome linked to amyloid and tau in Alzheimer's disease progression. https://pubmed.ncbi.nlm.nih.gov/27777997/ Proteomics. 2016 Dec; 16(23). ABSTRACT
Despite a key role of amyloid-beta (Aβ) in Alzheimer’s disease (AD), mechanisms that link Aβ plaques to tau neurofibrillary tangles and cognitive decline still remain poorly understood. The purpose of this study was to quantify proteins in the sarkosyl-insoluble brain proteome correlated with Aβ and tau insolubility in the asymptomatic phase of AD (AsymAD) and through mild cognitive impairment (MCI) and symptomatic AD. Employing label-free mass spectrometry based proteomics, we quantified 2,711 sarkosyl-insoluble proteins across the prefrontal cortex from 35 individual cases representing control, AsymAD, MCI and AD. Significant enrichment of Aβ and tau in AD was observed, which correlated with neuropathological measurements of plaque and tau tangle density, respectively. Pairwise correlation coefficients were also determined for all quantified proteins to Aβ and tau, across the 35 cases. Notably, 6 of the 10 most correlated proteins to Aβ were U1 small nuclear ribonucleoproteins (U1 snRNPs). Three of these U1 snRNPs (U1A, SmD and U1-70K) also correlated with tau consistent with their association with tangle pathology in AD. Thus, proteins that cross-correlate with both Aβ and tau, including specific U1 snRNPs, may have potential mechanistic roles in linking Aβ plaques to tau tangle pathology during AD progression.
Giri A, Mok KY, Jansen I, Sharma M, Tesson C, Mangone G, Lesage S, Bras JM, Shulman JM, Sheerin UM; International Parkinson's Disease Consortium (IPDGC); Díez-Fairen M, Pastor P, Martí MJ, Ezquerra M, Tolosa E, Correia-Guedes L, Ferreira J, Amin N, van Duijn CM, van Rooij J, Uitterlinden AG, Kraaij R, Nalls M, Simón-Sánchez J. Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population. https://pubmed.ncbi.nlm.nih.gov/27818000/ Neurobiology of Aging. 2017 Feb; 50. ABSTRACT
Mutations in TMEM230 have recently been associated to Parkinson's disease (PD). To further understand the role of this gene in the Caucasian population, we interrogated our large repository of next generation sequencing data from unrelated PD cases and controls, as well as multiplex families with autosomal dominant PD. We identified 2 heterozygous missense variants in 2 unrelated PD cases and not in our control database (p.Y106H and p.I162V), and a heterozygous missense variant in 2 PD cases from the same family (p.A163T). However, data presented herein is not sufficient to support the role of any of these variants in PD pathology. A series of unified sequence kernel association tests also failed to show a cumulative effect of rare variation in this gene on the risk of PD in the general Caucasian population. Further evaluation of genetic data from different populations is needed to understand the genetic role of TMEM230 in PD etiology.
Chouhan AK, Guo C, Hsieh Y-C, Ye H, Senturk M, Zuo Z, Li Y, Chatterjee S, Botas J, Jackson GR, Bellen HJ, Shulman JM. Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease. https://pubmed.ncbi.nlm.nih.gov/27338814/ Acta Neuropathologica Communications. 2016 Jun 23; 4(1). ABSTRACT
Common neurodegenerative proteinopathies, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by the misfolding and aggregation of toxic protein species, including the amyloid beta (Aβ) peptide, microtubule-associated protein Tau (Tau), and alpha-synuclein (αSyn) protein. These factors also show toxicity in Drosophila; however, potential limitations of prior studies include poor discrimination between effects on the adult versus developing nervous system and neuronal versus glial cell types. In addition, variable expression paradigms and outcomes hinder systematic comparison of toxicity profiles. Using standardized conditions and medium-throughput assays, we express human Tau, Aβ or αSyn selectively in neurons of the adult Drosophila retina and monitor age-dependent changes in both structure and function, based on tissue histology and recordings of the electroretinogram (ERG), respectively. We find that each protein causes a unique profile of neurodegenerative pathology, demonstrating distinct and separable impacts on neuronal death and dysfunction. Strikingly, expression of Tau leads to progressive loss of ERG responses whereas retinal architecture and neuronal numbers are largely preserved. By contrast, Aβ induces modest, age-dependent neuronal loss without degrading the retinal ERG. αSyn expression, using a codon-optimized transgene, is characterized by marked retinal vacuolar change, progressive photoreceptor cell death, and delayed-onset but modest ERG changes. Lastly, to address potential mechanisms, we perform transmission electron microscopy (TEM) to reveal potential degenerative changes at the ultrastructural level. Surprisingly, Tau and αSyn each cause prominent but distinct synaptotoxic profiles, including disorganization or enlargement of photoreceptor terminals, respectively. Our findings highlight variable and dynamic properties of neurodegeneration triggered by these disease-relevant proteins in vivo, and suggest that Drosophila may be useful for revealing determinants of neuronal dysfunction that precede cell loss, including synaptic changes, in the adult nervous system.
Valenca GT, Srivastava GP, Oliveira-Filho J, White CC, Yu L, Schneider JA, Buchman AS, Shulman JM, Bennett DA, De Jager PL. The Role of MAPT Haplotype H2 and Isoform 1N/4R in Parkinsonism of Older Adults. https://pubmed.ncbi.nlm.nih.gov/27458716/ PLoS One. 2016 Jul 26; 11(7). ABSTRACT
Background and objective: Recently, we have shown that the Parkinson's disease (PD) susceptibility locus MAPT (microtubule associated protein tau) is associated with parkinsonism in older adults without a clinical diagnosis of PD. In this study, we investigated the relationship between parkinsonian signs and MAPT transcripts by assessing the effect of MAPT haplotypes on alternative splicing and expression levels of the most common isoforms in two prospective clinicopathologic studies of aging. Materials and methods: using regression analysis, controlling for age, sex, study and neuropathology, we evaluated 976 subjects with clinical, genotyping and brain pathology data for haplotype analysis. For transcript analysis, we obtained MAPT gene and isoform-level expression from the dorsolateral prefrontal cortex for 505 of these subjects. Results: The MAPT H2 haplotype was associated with lower total MAPT expression (p = 1.2x10-14) and global parkinsonism at both study entry (p = 0.001) and proximate to death (p = 0.050). Specifically, haplotype H2 was primarily associated with bradykinesia in both assessments (p<0.001 and p = 0.008). MAPT total expression was associated with age and decreases linearly with advancing age (p<0.001). Analysing MAPT alternative splicing, the expression of 1N/4R isoform was inversely associated with global parkinsonism (p = 0.008) and bradykinesia (p = 0.008). Diminished 1N/4R isoform expression was also associated with H2 (p = 0.001). Conclusions: Overall, our results suggest that age and H2 are associated with higher parkinsonism score and decreased total MAPT RNA expression. Additionally, we found that H2 and parkinsonism are associated with altered expression levels of specific isoforms. These findings may contribute to the understanding of the association between MAPT locus and parkinsonism in elderly subjects and in some extent to age-related neurodegenerative diseases.
Ali YO, Allen HM, Yu L, Li-Kroeger D, Bakhshizadehmahmoudi D, Hatcher A, McCabe C, Xu J, Bjorklund N, Taglialatela G, Bennett DA, De Jager PL, Shulman JM, Bellen HJ, Lu H-C. NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies. https://pubmed.ncbi.nlm.nih.gov/27254664/ PLoS Biology. 2016 Jun 2; 14(6). ABSTRACT
Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is neuroprotective in numerous preclinical models of neurodegeneration. Here, we show that brain nmnat2 mRNA levels correlate positively with global cognitive function and negatively with AD pathology. In AD brains, NMNAT2 mRNA and protein levels are reduced. NMNAT2 shifts its solubility and colocalizes with aggregated Tau in AD brains, similar to chaperones, which aid in the clearance or refolding of misfolded proteins. Investigating the mechanism of this observation, we discover a novel chaperone function of NMNAT2, independent from its enzymatic activity. NMNAT2 complexes with heat shock protein 90 (HSP90) to refold aggregated protein substrates. NMNAT2's refoldase activity requires a unique C-terminal ATP site, activated in the presence of HSP90. Furthermore, deleting NMNAT2 function increases the vulnerability of cortical neurons to proteotoxic stress and excitotoxicity. Interestingly, NMNAT2 acts as a chaperone to reduce proteotoxic stress, while its enzymatic activity protects neurons from excitotoxicity. Taken together, our data indicate that NMNAT2 exerts its chaperone or enzymatic function in a context-dependent manner to maintain neuronal health.
2015 Farlow, JL, Robak, LA, Hetrick, K, Bowling, K, Boerwinkle, E, Akdemir, ZC, Gambin, T, Gibbs, RA, Gu, S, Jain, P, Jankovic, J, Jhangiani, SN, Kaw, K, Lin, H, Ling, H, Liu, Y, Lupski, JR, Muzny, D, Porter, P, Pugh, E, White, J, Doheny, K, Myers, RM, Shulman, JM*, Foroud, T*. Whole exome sequencing identifies candidate genes for Parkinson’s disease. JAMA Neurology. Epub ahead of print, doi: 10.1001/jamaneurol.2015.3266 PDF Editorial by Toft and Ross Shulman, JM. Drosophila and experimental neurology in the post-genomic era. Experimental Neurology. 2015; Epub ahead of print, doi: 10.1016/j.expneurol.2015.03.016 PDF Debette, S, Ibrahim-Verbaas, CA, Bressler, J, Schuur, M, Smith, A, Bis, JC, Davies, G, Wolf, C, Gudnason, V, Chibnik, LB, Yang, Q, deStefano, A, de Quervain, DJF, Srikanth, V, Lahti, J, Grabe, HJ, Smith, JA, Priebe, L, Yu, L, Karbalai, N, Hayward, C, Wilson, JF, Becker, J, Stegle, O, Mather, KA, Chouraki, V, Sun, Q, Rose, LM, Resnick, S, Oldmeadow, C, Kirin, M, Wright, AF, Jonsdottir, MK, Au, R, Becker, A, Amin, N, Nalls, MA, Turner, ST, Kardia, SLR, Oostra, B, Windham, G, Coker, LH, Zhao, W, Knopman, DS, Heiss, G, Griswold, ME, Gottesman, RF, Vitart, V, Hastie, ND, Zgaga, L, Rudan, I, Polasek, O, Holliday, EG, Schofield, P, Hoan Choi, S, Tanaka, T, An, Y, Perry, RT, Kennedy, RE, Sale, MM, Wang, J, Wadley, VG, Liewald, DC, Ridker, PM, Gow, AJ, Pattie, A, Starr, JM, Porteous, D, Liu, X, Thomson, R, Armstrong, NJ, Eiriksdottir, G, Assareh, AA, Kochan, NA, Widen, E, Palotie, A, Hsieh, Y-C, Eriksson, JG, Vogler, C, van Swieten, JC, Shulman, JM, Beiser, A, Rotter, J, Schmidt, CO, Hoffman, W, Nothen, MM, Ferrucci, L, Attia, J, Uitterlinden, AG, Amouyel, P, Dartigues, J-F, Amieva, H, Raikkonen, K, Garcia, M, Wolf, PA, Hofman, A, Longstreth, WT, Psaty, BM, Boerwinkle, E, De Jager, PL, Sachdev, PS, Schmidt, R, Breteler, MMB, Teurner, A, Lopez, OL, Cichon, S, Chasman, DI, Grodstein, F, Muller-Myhsok, B, Tzourio, C, Papassotiropoulos, A, Bennett, DA, Ikram, MA, Deary, IJ, van Duijn, CM, Launer, L, Fitzpatrick, AL, Seshadri, S, and Mosley, TH for the CHARGE Consortium. Genome-wide studies of verbal declarative memory in non-demented older people: the cohorts for heart and aging research in genomic epidemiology consortium. Biol Psychiatry. 2015; 77:749-763. PDF Ibrahim-Verbaas, CA, Bressler, J, Debette, S, Schuur, M, Smith, AV, Bis, JC, Davies, G, Trompet, S, Smith, JA, Wolf, C, Chibnik, LB, liu, Y, Vitart, V, Kirin, M, Petrovic, K, Polasek, O, Zgaga, L, Fawns-Ritchie, C, Hoffman, P, Karjalainen, J, Lahti, J, Llewellyn, DJ, Schmidt, CO, Mather, KA, Mather, KA, Chouraki, V, Sun, Q, Resnick, SM, Rose, LM, Oldmeadow, C, Stewar, M, Smith, BH, Gudnason, V, Yang, Q, Mirza, SS, Jukema, JW, De Jager, PL, Harris, TB, Liewald, DC, Amin, N, Coker, LH, Stegle, O, Lopez, OL, Schmidt, R, Teumer, A, Ford, I, Karbalai, N, Becker, JT, Jonsdottir, MK, Au, R, Fehrmann, RSN, Herms, S, Nalls, M, Zhao, W, Turner, ST, Yaffe, K, Lohman, K, van Swieten, JC, Kardia, SLR, Knopman, DS, Meeks, WM, Heiss, G, Holliday, EG, Schofield, PW, Tanaka, T, Stott, DJ, Wang, J, Ridker, P, Gow, AJ, Pattie, A, Starr, JM, Hocking, LJ, Armstrong, NJ, McLachlan, S, Shulman, JM, Pilling, LC, Eiriksdottir, G, Scott, RJ, Kochan, NA, Palotie, A, Hsieh, Y-C, Eriksson, JG, Penman, A, Gottesman, RF, Oostra, BA, Yu, L, DeStefano, AL, Beiser, A, Garcia, M, Rotter, JI, Nothen, MM, Hofman, A, Slagboom, PE, Westendorp, RGJ, Buckley, BM, Wolf, PA, Uitterlinden, AG, Psaty, BM, Grabe, HJ, Bandinelli, S, Chasman, DI, Grodstein, F, Raikkonen, Lambert, J-C, Porteous, Generation Scotland, Price, JF, Sachdev, PS, Ferrucci, Attia, JR, Rudan, I, Hayward, C, Wright, AF, Wilson, JF, Cichon, S, Franke, L, Schmidt, H, Ding, J, de Craen, AJM, Fornage, M, Bennett, DA, Deary, IJ, Ikram, MA, Launer, LJ, Fitzpatrick, AL, Seshadri, S, van Duijn, CM, and Mosley, TH. GWAS for executive function and processing speed suggests involvement of the CADM2 gene. Mol Psychiatry 2015; Epub ahead of print, doi: 10.1038/mp.2015.37 PDF 2014 Buchman, AS, Yu, L, Wilson, RS, Shulman, JM, Boyle, PA, Bennett, DA. Harm avoidance is associated with the rate of progressive parkinsonism in community-dwelling older persons: a prospective cohort study. BMC Geriatrics. 2014; 14:54. PDF Haelterman, NA, Yoon, WH, Sandoval, H, Jaiswal, M, Shulman, JM, Bellen, HJ. A mitocentric view of Parkinson’s Disease. Annual Review of Neuroscience. 2014; Epub ahead of print. PDF Buchman, AS, Yu, L, Wilson, RS, Shulman, JM, Boyle, PA, Bennett, DA. Harm avoidance is associated with the rate of progressive parkinsonism in community-dwelling older persons: a prospective cohort study. BMC Geriatrics. 2014; 14:54. PDF Shulman, JM, Yu, L, Buchman, AS, Evans, DA, Schneider, JA, Bennett, DA, De Jager, PL. Association of Parkinson Disease susceptibility loci with mild parkinsonian signs in older persons. JAMA Neurology. 2014; 71:429-35. PDF Supplement Shulman, JM, Imboywa, S, Giagtzoglou, N, Powers, MP, Hu, Yanhui, Devenport, D, Chipendo, P, Chibnik, LB, Diamond A, Perrimon, N, Brown, NH, De Jager PL, Feany, MB. Functional screening in Drosophila identifies Alzheimer’s disease susceptibility genes and implicates Tau-mediated mechanisms. Human Molecular Genetics. 2014; 23:870-877 PDF Supplement-1 Supplement-2 Sherva, R, Tripodis, Y, Bennett, D, Chibnik, LB, Crane, PK, De Jager, P, Farrer, LA, Saykin, AJ, Shulman, JM, Green, RC, ADNI. Genomewide Association Study of the Rate of Cognitive Decline in Alzheimer's Disease. Alzheimer's & Dementia. 2014; 10:45-52. PDF 2013
Chou, SH*, Shulman, JM*, Keenan, B, Secor, EA Buchman, AS, Schneider, JA, Bennett, DA, De Jager, PL. Genetic susceptibility for ischemic infarction and arteriosclerosis based on neuropathologic evaluations. Cerebrovascular Diseases. 2013; 36:181-8. PDF Shulman, JM, Chen, K, Keenan, BT, Chibnik, LB, Thiyyagura, P, Liu, X, Roontive, A, Yu, L, McCabe, C, Patsopoulos, NA, Corneveaux, JJ, Huentelman, MJ, ADNI, Evans, DA, Schneider, JA, Reimain, EM, De Jager, PL, Bennett, DA. Genetic susceptibility for Alzheimer's disease neuritic plaque pathology. JAMA Neurology. 2013; 70:1150-7. PDF Cruchaga, C, Kauwe, JSK, Harari, O, Jin, SC, Shulman, JM, De Jager, PL, Chibnik, LB, Bennett, DA, Arnold, SE, Van Deerlin, V, Lee, VM, Shaw, L, Trojanowski, J, Haines, JL, Mayeux, R, Pericak-Vance, MA, Farrer, LA, Schellenberg, GD, Peskind, ER, Galasko, D, Mayo, K, Bertelsen, S, Bailey, M, McKean, D, Fagan, AM, Holtzman, DM, Morris, JC, Alzheimer's Disease Genetic Consortium, Alzheimer's Disease Neuroimaging Initiative, GERAD Consortium, Goate, AM. A genome-wide association study for cerebrospinal fluid tau and phospho-tau levels identifies new candidate variants implicated in risk for Alzheimer's Disease. Neuron. 2013; 78:256-268. PDF 2012 Biffi, A, Shulman, JM, Jagiella, JM, Cortellini, L, Ayres, A, Schwab, K, Brown, DL, Silliman, SL, Selim, M, Worrall, BB, Meschia, JF, Slowik, A, De Jager, PL, Greenberg, SM, Schneider, JA, Bennett, DA, Rosand, J. Genetic Variation at CR1 Increases Risk and Severity of Cerebral Amyloid Angiopathy. Neurology. 2012; 78:334-341. PDF Buchman, AS, Shulman, JM, Nag, S, Leurgans, SE, Schneider, JA, and Bennett, DA. Nigral Pathology and Parkinsonian Signs in Elders without Parkinson's Disease. Annals of Neurology. 2012; 71:258-266. PDF De Jager, PL*, Shulman, JM*, Chibnik, LB*, Keenan, BT, Raj, T, Wilson, RS, Yu, L, Leurgans, SE, Tran, D, Aubin, C, Corneveaux, JJ, Huentelman, MJ, ADNI, Myers, AJ, Hardy, JA, Reiman, EM, Bennett, DA, and Evans, DA. A genome-wide scan for common variants affecting rate of age-related cognitive decline. Neurobiology of Aging. 2012; 33: 1017.e1-1017.e15. *Equal contribution. PDF Yu, L, Shulman, JM, Chibnik, L, Leurgans, S, Schneider, JA, De Jager, PL, Bennett, DA. The CETP I405V polymorphism is associated with increased risk of Alzheimer’s disease. Aging Cell. 2012; 11:228-233. PDF Raj, T, Shulman, JM, Keenan, BT, Chibnik, LB, Evans, DA, Bennett, DA, Stranger, BE, and De Jager, PL. Alzheimer’s disease susceptibility: evidence for a protein network under natural selection. American Journal of Human Genetics. 2012; 90:720-726. PDF Keenan, BT, Shulman, JM, Chibnik, LB, Raj, T, Tran, D, Sabuncu, MR, ADNI, Allen, A, Myers, AJ, Hardy, JA, Huentelman, MJ, Reiman, EM, Evans, DA, Bennett, DA, De Jager, PL. Functional fine-mapping of the CR1 locus identifies a causal variant. Human Molecular Genetics. 2012; 21:2377-2388. PDF Bis*, JC, DeCarli*, C, Smith*, AV, van der Lijn*, F, Crivello*, F, Fornage*, M, Debette*, S, Shulman, JM et al. Genome-wide association studies implicate loci on Chromosome 12 in hippocampal volume. Nature Genetics. 2012; 44:545-551. *Equal contribution. PDF Valant V, Keenan, BT, Anderson, CD, Shulman, JM, Devan, WJ, Ayres, AM, Schwab, K, Goldstein, JN, Viswanathan, A, Greenberg, SM, Bennett, DA, De Jager, PL, Rosand, J, Biffi, A, ADNI. TOMM40 in CAA-related ICH: Comparative Genetic Analysis with Alzheimer’s Disease. Translational Stroke Research. 2012; 3(S1):102-112. PDF
Hek, K, Demirkan, A, Lahti, J, ... Shulman, JM, ... Newman, AB, Tiemeier, H, Murabito, J. A Genome-Wide Association Study of Depressive Symptoms. Biological Psychiatry. In press. PDF Buchman, AS, Nag, S, Shulman, JM, Lim, ASP, VanderHorst, VGJM, Leurgans, SE, Schneider, JA, Bennett, DA. Locus Coeruleus Neuron Density and Parkinsonism in Older Adults without Parkinson’s Disease. Movement Disorders. 2012; 27:1625-1631. PDF Buchman, AS, Shulman, JM, Leurgans, SE, Schneider, JA, and Bennett, DA. Reply. Annals Neurol 2012; 72:298. Shulman, JM and Schneider, JA. Molecular mechanisms of cortical degeneration in Parkinson disease. Neurology. 2012; 79: 1750-1751. PDF 2011 Shulman, JM, Chipendo, PC, Chibnik, L.B., Keenan, B.T., Aubin, C, Tran, D, Kramer, P, Schneider, J.A., Bennett, DA, Feany, MB, De Jager, PL. Functional screening of Alzheimer pathology genome-wide association signals in Drosophila. American Journal of Human Genetics. 2011; 88:232-238. PDF Chibnik, LB, Shulman, JM, Leurgans, S, Shneider, JA, Wilson, RS, Tran, D, Aubin, C, Huentelman, MJ, Reiman, EM, Evans, DA, Bennett, DA, De Jager, PL. The Alzheimer’s susceptibility locus CR1 is associated with increased amyloid plaque burden and age-related cognitive decline. Annals of Neurology. 2011; 69:560-569. PDF Treusch, S, Hamamichi, S, Goodman, JL, Matlack, KES, Chung, CY, Baru, V, Shulman, JM, Parrado, A, Bevis, BJ, Valastyan, JS, Han, H, Lindhagen-Persson, M, Reiman, EM, Evans, DA, Bennett, DA, Olofsson, A, De Jager, PL, Tanzi, RE, Caldwell, KA, Caldwell, Shulman, JM, De Jager, PL, Feany, MB. Parkinson’s disease: Genetics and Pathogenesis. Annual Reviews of Pathology: Mechanisms of Disease 2011; 6:193-222. PDF 2010 Shulman, JM, Chibnik, LB, Aubin, C, Schneider, J, De Jager, P, and Bennett, D. Intermediate phenotypes identify divergent pathways to Alzheimer’s disease. PLoS ONE 2010; 5(6): e11244. PDF Xia, Z, Chibnik, LB, Glanz, BI, Liguori, M., Shulman, JM, Tran, D, Khoury, SJ, Chitnis, T, Holyoak, T, Weiner, HL, Guttmann, CRG, De Jager, PL. An Alzheimer's disease Risk Allele in PCK1 Influences Brain Atrophy in Multiple Sclerosis. PLoS ONE 2010; 5(11): e14169. PDF Corneveaux, JJ, Myers, AJ, Allen, AN, Pruzin, JJ, Ramirez, M, Engel, A, Nalls, MA, Chen, K, Lee, W, Chewning, K, Villa, SE, Meechoovet, HB, Gerber, JD, Frost, D, Benson, HL, O'Reilly, S, Chibnik, LB, Shulman, JM, Singleton, A, Craig, DW, Van Keuren-Jensen, KR, Dunckley, T, Bennett, DA, De Jager, PL, Heward, C, Hardy, J, Reiman, EM, Huentelman, MJ. Association of CR1, CLU, and PICALM with Alzheimer's disease in a cohort of clinically and characterized and neuropathologically verified individuals. Human Molecular Genetics 2010; 19:3295-3301. PDF Shulman, JM. Incidence and Risk for Dementia in Parkinson Disease. Journal Watch: Neurology 2010; 12(4):28.
Shulman, JM and De Jager, P.L. Evidence for a common pathway linking neurodegenerative diseases. Nature Genetics 2009; 41:1261-1262. PDF 2008 Alcalay, RN, Shulman, JM, and Plotkin, SR. Ramsay Hunt syndrome in a patient with metastatic lung cancer to brain. Journal of Neurooncology 2008; 86:55-56. PDF 2007 Steinhilb, ML, Dias-Santagata, D, Mulkearns, EE, Shulman, JM, Biernat, J, Mandelkow, EM and Feany, MB. S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila. Journal of Neuroscience Research 2007;85:1271-1278. PDF 2006 Khurana, V, Lu, Y, Steinhilb, M, Oldham, S, Shulman, JM, and Feany MB. TOR-mediated cell cycle activation causes neurodegeneration in a Drosophila tauopathy model. Current Biology 2006; 16:1-12. PDF 2005 Shulman, JM. Wing of Fly, Tail of Rodent, Scale of Fish, and Pinch of Yeast: Cooking Up the Ultimate Animal Model in Movement Disorders. Moving Along 2005;7(1):1. 2004 Shulman, JM. Surgical Lessons from Shakespeare. Current Surgery 2004; 61:96-97. 2003 Doerflinger, H, Benton, R, Shulman, JM, and St Johnston, D. The role of PAR-1 in regulating the polarised microtubule cytoskeleton in the Drosophila follicular epithelium. Development 2003; 130:3965-3975. PDF Shulman, JM and Feany, MB. Genetic modifiers of tauopathy in Drosophila. Genetics 2003; 165:1233-1242. PDF
Shulman, JM, Shulman, LM, Weiner, WJ, and Feany, MB. From fruit fly to bedside: translating lessons from Drosophila models of neurodegenerative disease. Current Opinion in Neurology 2003; 16:443-449. PDF 2002 Tree, DRP, Shulman, JM, Gubb, D, and Axelrod, JD. Prickle mediates feedback amplification to generate asymmetric planar cell polarity signaling. Cell 2002;109:371-381. PDF 2001 Huynh, J-R, Shulman, JM, Benton, R, and St Johnston, D. PAR-1 is required for the maintenance of oocyte fate in Drosophila. Development 2001; 128:1201-1209. PDF Wittman, CW, Wszolek, MF, Shulman, JM, Salvaterra, PM, Lewis, J, Hutton, M., Feany, MB. Tauopathy in Drosophila: Neurodegeneration without neurofibrillary tangles. Science 2001; 293:711-714. PDF 2000 
Shulman, JM, Benton, R., and St Johnston, D. A Drosophila homolog of C. elegans PAR-1 organizes the oocyte cytoskeleton and directs oskar mRNA localization to the posterior pole. Cell 2000; 101:377-388. PDF 1999 Shulman, JM and St Johnston, D. Pattern formation in single cells. Trends in Cell Biology 1999; 9:M60-M64. PDF 1998 Axelrod, JD, Miller, JR, Shulman, JM, Moon, RT, and Perrimon, N. Differential recruitment of Dishevelled provides signaling specificity in the Planar Cell Polarity and Wingless signaling pathways. Genes and Development 1998; 12:2610-2622. PDF Shulman, JM, Perrimon, N., and Axelrod, JD. Frizzled Signaling and the Developmental Control of Cell Polarity. Trends in Genetics 1998; 14:452-458. |
Lim, ASP, Chang, AM, Shulman, JM, Raj, T, Chibnik, LB, Myers, AJ, Buchman, AS, Bennett, DA, Cain, SW, Czeisler, CA, Duffy, JF, Saper, CB, De Jager, PL. A common polymorphism near PER1 and the timing of human behavioral rhythms. Annals of Neurology. 2012; 72:324-334. PMCID: PMC3464954. 
GA, Lindquist, S. A yeast model establishes a functional connection between Aβ Toxicity and endocytic trafficking and Alzheimer’s Disease risk factors. Science. 2011; 334:1241-1245. 
2009
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