Roy N Alcalay1,2, Victoria Mallett3, Benoît Vanderperre4, Omid Tavassoly4, Yves Dauvilliers5, Richard Y J Wu3,6, Jennifer A Ruskey3,7, Claire S Leblond3,8, Amirthagowri Ambalavanan3,8, Sandra B Laurent3,7, Dan Spiegelman3,7, Alexandre Dionne-Laporte3,7, Christopher Liong1, Oren A Levy1, Stanley Fahn1, Cheryl Waters1, Sheng-Han Kuo1, Wendy K Chung9,10, Blair Ford1, Karen S Marder1, Un Jung Kang1, Sharon Hassin-Baer11,12,13, Lior Greenbaum11,14,15, Jean-Francois Trempe16, Pavlina Wolf17, Petra Oliva17, Xiaokui Kate Zhang17, Lorraine N Clark2,18,19, Melanie Langlois20,21, Patrick A Dion3,7, Edward A Fon4, Nicolas Dupre20,21, Guy A Rouleau3,7,8, Ziv Gan-Or3,7,8. 1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. 2. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA. 3. Montreal Neurological Institute, McGill University, Montréal, QC, Canada. 4. McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montréal, QC, Canada. 5. Sleep Unit, National Reference Network for Narcolepsy, Department of Neurology Hôpital-Gui-de Chauliac, CHU Montpellier, INSERM U1061, France. 6. Imperial College School of Medicine, Imperial College London, London, United Kingdom. 7. Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada. 8. Department of Human Genetics, McGill University, Montréal, QC, Canada. 9. Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA. 10. Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, USA. 11. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 12. Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel. 13. Movement Disorders Institute, Sheba Medical Center, Tel Hashomerf, Israel. 14. The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel. 15. The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel. 16. Department of Pharmacology & Therapeutics, McGill University, Montréal, Québec, Canada. 17. Translational Science, Sanofi, Framingham, MA, USA. 18. Laboratory of Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA. 19. Department of Pathology and Cell Biology, Columbia University, New York, NY, USA. 20. Axe neurosciences du CHU de Québec - Université Laval, Québec, QC, Canada. 21. Faculty of Medicine, Department of Medicine, Laval University, Québec, QC, Canada.
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.
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 PDpatients 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 PDpatients 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 PDpatients, 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.
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