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SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease.
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.
Afiliação
  • Alcalay RN; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Mallett V; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
  • Vanderperre B; Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Tavassoly O; McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Dauvilliers Y; McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Wu RYJ; Sleep Unit, National Reference Network for Narcolepsy, Department of Neurology Hôpital-Gui-de Chauliac, CHU Montpellier, INSERM U1061, France.
  • Ruskey JA; Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Leblond CS; Imperial College School of Medicine, Imperial College London, London, United Kingdom.
  • Ambalavanan A; Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Laurent SB; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
  • Spiegelman D; Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Dionne-Laporte A; Department of Human Genetics, McGill University, Montréal, QC, Canada.
  • Liong C; Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Levy OA; Department of Human Genetics, McGill University, Montréal, QC, Canada.
  • Fahn S; Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Waters C; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
  • Kuo SH; Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Chung WK; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
  • Ford B; Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
  • Marder KS; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
  • Kang UJ; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Hassin-Baer S; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Greenbaum L; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Trempe JF; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Wolf P; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Oliva P; Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Zhang XK; Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Clark LN; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Langlois M; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Dion PA; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Fon EA; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Dupre N; Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel.
  • Rouleau GA; Movement Disorders Institute, Sheba Medical Center, Tel Hashomerf, Israel.
  • Gan-Or Z; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Mov Disord ; 34(4): 526-535, 2019 04.
Article em En | MEDLINE | ID: mdl-30788890
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Esfingomielina Fosfodiesterase / Encéfalo / Predisposição Genética para Doença / Alfa-Sinucleína Limite: Aged / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2019 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Esfingomielina Fosfodiesterase / Encéfalo / Predisposição Genética para Doença / Alfa-Sinucleína Limite: Aged / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2019 Tipo de documento: Article