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

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/Montpel...

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Published in:	Movement disorders Vol. 34; no. 4; pp. 526 - 535
Main Authors:	Alcalay, Roy N., Mallett, Victoria, Vanderperre, Benoît, Tavassoly, Omid, Dauvilliers, Yves, Wu, Richard Y.J., Ruskey, Jennifer A., Leblond, Claire S., Ambalavanan, Amirthagowri, Laurent, Sandra B., Spiegelman, Dan, Dionne‐Laporte, Alexandre, Liong, Christopher, Levy, Oren A., Fahn, Stanley, Waters, Cheryl, Kuo, Sheng‐Han, Chung, Wendy K., Ford, Blair, Marder, Karen S., Kang, Un Jung, Hassin‐Baer, Sharon, Greenbaum, Lior, Trempe, Jean‐Francois, Wolf, Pavlina, Oliva, Petra, Zhang, Xiaokui Kate, Clark, Lorraine N., Langlois, Melanie, Dion, Patrick A., Fon, Edward A., Dupre, Nicolas, Rouleau, Guy A., Gan‐Or, Ziv
Format:	Journal Article
Language:	English
Published:	Hoboken, USA John Wiley & Sons, Inc 01-04-2019 Wiley
Subjects:	acid sphingomyelinase Aged alpha-Synuclein - metabolism Brain - metabolism Brain - pathology Female Gene Knockdown Techniques Genetic Predisposition to Disease genetics HeLa Cells Human health and pathology Humans Jews - genetics Life Sciences Male Middle Aged Mutation Neurons and Cognition Parkinson Disease - genetics Parkinson Disease - metabolism Parkinson Disease - pathology Parkinson's disease SMPD1 Sphingomyelin Phosphodiesterase - genetics α‐synuclein Parkinson's disease genetics SMPD1 acid sphingomyelinase α-synuclein
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Summary:	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
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC6469643 Jennifer A. Ruskey: 1B, 1C, 3B Melanie Langlois: 1C, 3B Cheryl Waters: 1C, 3B Victoria Mallett: 1B, 1C, 3B, 2A Christopher Liong: 1B, 3B These authors contributed equally to the work Jean-Francois Trempe: 1B, 1C, 3B Patrick A. Dion: 1B, 3B Dan Spiegelman: 1C, 3B Claire S. Leblond: 1C, 3B Karen S. Marder: 1C, 3B 1) Research project: A. Conception, B. Organization, C. Execution Alexandre Dionne-Laporte: 1C, 3B Wendy K. Chung: 2C, 3B Pavlina Wolf: 1B, 1C, 3A, 3B Blair Ford: 1C, 3B 3) Manuscript: A. Writing of the first draft, B. Review and Critique. Ziv Gan-Or: 1A, 1B, 2A, 2B, 2C, 3A, 3B Richard Y.J. Wu: 1B, 1C, 3B Sheng-Han Kuo: 1B, 3B Yves Dauvilliers: 1B, 2C, 3B Xiaokui Kate Zhang: 1A, 1B, 3B Stanley Fahn: 1C, 3B Sharon Hassin-Baer: 1B, 3B Un Jung Kang: 1C, 3B Lior Greenbaum: 1B, 3B Amirthagowri Ambalavanan: 1C, 2B, 2C, 3B Nicolas Dupre: 1A, 1B, 3B Guy A. Rouleau: 1B, 3B Edward A. Fon: 1A, 3B Lorraine N. Clark: 3B Sandra B. Laurent: 1B, 1C, 3B Petra Oliva: 1A, 1B, 3B Oren A. Levy: 1C, 3B Author roles 2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique Benoît Vanderperre: 1A, 1B, 1C, 2A, 2B, 3A, 3B Roy N. Alcalay: 1A, 1B, 1C, 2C, 3A. Omid Tavassoly: 1A, 1B, 1C, 2A, 2B, 3A, 3B
ISSN:	0885-3185 1531-8257 1531-8257
DOI:	10.1002/mds.27642