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

Autor: Roy N, Alcalay, Victoria, Mallett, Benoît, Vanderperre, Omid, Tavassoly, Yves, Dauvilliers, Richard Y J, Wu, Jennifer A, Ruskey, Claire S, Leblond, Amirthagowri, Ambalavanan, Sandra B, Laurent, Dan, Spiegelman, Alexandre, Dionne-Laporte, Christopher, Liong, Oren A, Levy, Stanley, Fahn, Cheryl, Waters, Sheng-Han, Kuo, Wendy K, Chung, Blair, Ford, Karen S, Marder, Un Jung, Kang, Sharon, Hassin-Baer, Lior, Greenbaum, Jean-Francois, Trempe, Pavlina, Wolf, Petra, Oliva, Xiaokui Kate, Zhang, Lorraine N, Clark, Melanie, Langlois, Patrick A, Dion, Edward A, Fon, Nicolas, Dupre, Guy A, Rouleau, Ziv, Gan-Or
Přispěvatelé: Columbia University Medical Center (CUMC), Columbia University [New York], McGill University = Université McGill [Montréal, Canada], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Montreal Neurological Institute and Hospital, Université Laval [Québec] (ULaval), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Nowak, Cécile
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Movement Disorders
Movement Disorders, Wiley, 2019, 34 (4), pp.526-535. ⟨10.1002/mds.27642⟩
ISSN: 0885-3185
1531-8257
Popis: International audience; 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.
Databáze: OpenAIRE
Externí odkaz: