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Cited by 110Parkinson's Disease Mechanisms and TreatmentsLysosomal Storage Disorders ResearchNeurological diseases and metabolism

SMPD1 mutations, activity, and α‐synuclein accumulation in Parkinson's disease

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Alcalay, Roy N., Mallett, Victoria, Vanderperre, Benoît, Tavassoly, Omid, Dauvilliers, Yves, Wu, Richard Y.J., Ruskey, Jennifer A., Leblond, Claire S. +26 more·2019·Movement Disorders
DOI 10.1002/mds.27642PMC PMC6469643
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Abstract

Background: SMPD1 (acid‐sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD. Methods: SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid‐sphingomyelinase activity was measured by a mass spectrometry‐based assay in the New York cohort. α‐Synuclein levels were measured in vitro following CRISPR/Cas9‐mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)‐M17 cells. Lysosomal localization of acid‐sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid‐sphingomyelinase structure was performed. Results: SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6‐8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid‐sphingomyelinase activity was associated with a 3.5‐ to 5.8‐year earlier onset of PD in the lowest quartile versus the highest quartile of acid‐sphingomyelinase activity ( P = 0.01‐0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α‐synuclein levels in HeLa and BE(2)‐M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid‐sphingomyelinase to the lysosome. Conclusions: Our results support an association between SMPD1 variants, acid‐sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid‐sphingomyelinase activity may lead to α‐synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society

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  • Lysosomes contain enzymes crucial for sphingolipid and carbohydrate catabolism.

    “Lysosomes also contain enzymes crucial for sphingolipid and carbohydrate catabolism.3”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [3]

    The Introduction (page not provided) identifies glucocerebrosidase and acid sphingomyelinase as lysosomal enzymes and says both hydrolyze sphingolipids in the lysosome. It does not address carbohydrate catabolism, so that part of the claim is unsupported by our copy. (LLM, conf=0.87)

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Research works printed but not linked: 31

  1. [1]Gan-Or Z, Dion PA, Rouleau GA. Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease. Autophagy 2015; 11(9): 1443– 1457. 26207393 PMC4590678
  2. [3]Alcalay RN, Levy OA, Waters CC, Glucocerebrosidase activity in Parkinson’s disease with and without GBA mutations. Brain 2015; 138(Pt 9): 2648– 2658. 26117366 PMC4564023
  3. [4]Clark LN, Ross BM, Wang Y, Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology 2007; 69(12): 1270– 1277. 17875915 PMC3624967
  4. [5]Gan-Or Z, Amshalom I, Kilarski LL, Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology 2015; 84(9): 880– 887. 25653295 PMC4351661
  5. [6]Gan-Or Z, Giladi N, Rozovski U, Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology 2008; 70(24): 2277– 2283. 18434642
  6. [7]Lesage S, Anheim M, Condroyer C, Large-scale screening of the Gaucher’s disease-related glucocerebrosidase gene in Europeans with Parkinson’s disease. Hum Mol Genet 2011; 20(1): 202– 210. 20947659
  7. [8]Neumann J, Bras J, Deas E, Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain 2009; 132(Pt 7): 1783– 1794. 19286695 PMC2702833
  8. [9]Sidransky E, Nalls MA, Aasly JO, Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 2009; 361(17): 1651– 1661. 19846850 PMC2856322
  9. [10]Clark LN, Chan R, Cheng R, Gene-wise association of variants in four lysosomal storage disorder genes in neuropathologically confirmed Lewy body disease. PLoS One 2015; 10(5): e0125204. 25933391 PMC4416714
  10. [11]Dagan E, Schlesinger I, Ayoub M, The contribution of Niemann-Pick SMPD1 mutations to Parkinson disease in Ashkenazi Jews. Parkinsonism Relat Disord 2015; 21(9): 1067– 1071. 26169695
  11. [12]Deng S, Deng X, Song Z, Systematic Genetic Analysis of the SMPD1 Gene in Chinese Patients with Parkinson’s Disease. Mol Neurobiol 2015. 26377108
  12. [13]Foo JN, Liany H, Bei JX, Rare lysosomal enzyme gene SMPD1 variant (p.R591C) associates with Parkinson’s disease. Neurobiol Aging 2013; 34(12): 2890 e2813– 2895. 23871123
  13. [14]Gan-Or Z, Orr-Urtreger A, Alcalay RN, Bressman S, Giladi N, Rouleau GA. The emerging role of SMPD1 mutations in Parkinson’s disease: Implications for future studies. Parkinsonism Relat Disord 2015; 21(10): 1294– 1295. 26320887
  14. [15]Gan-Or Z, Ozelius LJ, Bar-Shira A, The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease. Neurology 2013; 80(17): 1606– 1610. 23535491 PMC3662322
  15. [16]Robak LA, Jansen IE, van Rooij J, Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease. Brain 2017. PMC5841393 29140481
  16. [17]Ylonen S, Siitonen A, Nalls MA, Genetic risk factors in Finnish patients with Parkinson’s disease. Parkinsonism Relat Disord 2017. PMC5812481 29029963
  17. [18]Zampieri S, Filocamo M, Pianta A, SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants. Hum Mutat 2015. 26499107
  18. [19]Schuchman EH, Wasserstein MP. Types A and B Niemann-Pick disease. Best Pract Res Clin Endocrinol Metab 2015; 29(2): 237– 247. 25987176
  19. [20]Sakanaka K, Waters CH, Levy OA, Knowledge of and interest in genetic results among Parkinson disease patients and caregivers. J Genet Couns 2014; 23(1): 114– 120. 23748874 PMC3808456
  20. [21]Olivova P, Cullen E, Titlow M, An improved high-throughput dried blood spot screening method for Gaucher disease. Clin Chim Acta 2008; 398(1–2): 163– 164. 18812173
  21. [22]Reuser AJ, Verheijen FW, Bali D, The use of dried blood spot samples in the diagnosis of lysosomal storage disorders--current status and perspectives. Mol Genet Metab 2011; 104(1–2): 144– 148. 21831684
  22. [24]Lee BR, Kamitani T. Improved immunodetection of endogenous alpha-synuclein. PLoS One 2011; 6(8): e23939. 21886844 PMC3158774
  23. [25]Gorelik A, Illes K, Heinz LX, Superti-Furga G, Nagar B. Crystal structure of mammalian acid sphingomyelinase. Nat Commun 2016; 7: 12196. 27435900 PMC4961792
  24. [26]Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N Engl J Med 2004; 351(19): 1972– 1977. 15525722
  25. [27]Zimran A, Neudorfer O, Elstein D. The glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N Engl J Med 2005; 352(7): 728– 731; author reply 728–731. 15719452
  26. [28]Lerche S, Schulte C, Srulijes K, Cognitive impairment in Glucocerebrosidase (GBA)-associated PD: Not primarily associated with cerebrospinal fluid Abeta and Tau profiles. Mov Disord 2017; 32(12): 1780– 1783. 29094781
  27. [29]Brockmann K, Srulijes K, Pflederer S, GBA-associated Parkinson’s disease: reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord 2015; 30(3): 407– 411. 25448271
  28. [30]Gaare JJ, Nido GS, Sztromwasser P, Rare genetic variation in mitochondrial pathways influences the risk for Parkinson’s disease. Mov Disord 2018; 33(10): 1591– 1600. 30256453 PMC6282592
  29. [31]Rhein C, Naumann J, Muhle C, The Acid Sphingomyelinase Sequence Variant p.A487V Is Not Associated With Decreased Levels of Enzymatic Activity. JIMD Rep 2013; 8: 1– 6. 23430512 PMC3565629
  30. [32]Duran R, Mencacci NE, Angeli AV, The glucocerobrosidase E326K variant predisposes to Parkinson’s disease, but does not cause Gaucher’s disease. Mov Disord 2013; 28(2): 232– 236. 23225227 PMC4208290
  31. [33]Pankratz N, Beecham GW, DeStefano AL, Meta-analysis of Parkinson’s disease: identification of a novel locus, RIT2. Ann Neurol 2012; 71(3): 370– 384. 22451204 PMC3354734

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Authors
Alcalay, R. N., Mallett, V., Vanderperre, B., Tavassoly, O., Dauvilliers, Y., Wu, R. Y. J., Ruskey, J. A., Leblond, C. S., Ambalavanan, A., Laurent, S. B., Spiegelman, D., Dionne‐Laporte, A., Liong, C., Levy, O. A., Fahn, S., Waters, C., Kuo, S., Chung, W. K., Ford, B., Marder, K. S., Kang, U. J., Hassin‐Baer, S., Greenbaum, L., Trempe, J., Wolf, P., Oliva, P., Zhang, X. K., Clark, L. N., Langlois, M., Dion, P. A., Fon, E. A., Dupre, N., Rouleau, G. A., & Gan‐Or, Z.
Affiliations
  • Columbia University (US)
  • McGill University (CA)
  • Montreal Neurological Institute and Hospital (CA)
  • Inserm (FR)
  • Imperial College London (GB)
  • Columbia University Irving Medical Center (US)
  • Tel Aviv University (IL)
  • Department of Pharmacology & Therapeutics McGill University Montréal Québec Canada
  • Sanofi (United States) (US)
  • Axe neurosciences du CHU de Québec ‐ Université Laval Québec QC Canada
Corresponding author
Gan‐Or, Ziv
ORCID
Venue
Movement Disorders
Publisher
Wiley
Published
2019-02-20
Volume
34
Issue
4
Pages
526-535
ISSN
  • 0885-3185 (ISSN-L)
  • 1531-8257
DOI
10.1002/mds.27642
PMC
PMC6469643
OpenAlex
W2917598617
Cited by
110
References
2
Citations by year
2026: 10 · 2025: 10 · 2024: 15 · 2023: 20 · 2022: 14 · 2021: 15 · 2020: 15 · 2019: 11
FWCI
9.31
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Movement Disorders (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
Funders
  • Brookdale Foundation
  • Canadian Institutes of Health Research
  • Fonds de Recherche du Québec - Santé
  • Michael J. Fox Foundation for Parkinson's Research
  • National Institutes of Health (K02NS080915, UL1 TR000040)
  • Parkinson's Disease Foundation
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords
SMPD1, acid sphingomyelinase, Parkinson's disease, alpha-synuclein accumulation, Ashkenazi Jewish population, enzyme activity, lysosomal trafficking, dopaminergic neurons, genetic susceptibility, age of onset, CRISPR/Cas9 knockout
MeSH terms
Aged, Brain, Female, HeLa Cells, Humans, Jews, Male, Middle Aged, Mutation, Parkinson Disease, Sphingomyelin Phosphodiesterase, Genetic Predisposition to Disease, alpha-Synuclein, Gene Knockdown Techniques

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