SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease.
SMPD1
Parkinson's disease
acid sphingomyelinase
genetics
α-synuclein
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
14
02
2018
revised:
21
11
2018
accepted:
10
01
2019
pubmed:
23
2
2019
medline:
10
1
2020
entrez:
22
2
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 30788890
doi: 10.1002/mds.27642
pmc: PMC6469643
mid: NIHMS1017870
doi:
Substances chimiques
alpha-Synuclein
0
SMPD1 protein, human
EC 3.1.4.12
Sphingomyelin Phosphodiesterase
EC 3.1.4.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
526-535Subventions
Organisme : NIH HHS
ID : K02NS080915
Pays : United States
Organisme : Michael J. Fox Foundation for Parkinson's Research
Pays : International
Organisme : NINDS NIH HHS
ID : K02 NS080915
Pays : United States
Organisme : NINDS NIH HHS
ID : U10 NS077267
Pays : United States
Organisme : NIH HHS
ID : UL1 TR000040
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS101982
Pays : United States
Organisme : Brookdale Foundation
Pays : International
Organisme : Parkinson's Disease Foundation
Pays : International
Organisme : NINDS NIH HHS
ID : R03 NS096494
Pays : United States
Organisme : Canadian Consortium om Neurodegeneration in Aging (CCNA)
Pays : International
Organisme : Fonds de Recherche du Québec - Santé
Pays : International
Organisme : NCATS NIH HHS
ID : UL1 TR000040
Pays : United States
Organisme : NINDS NIH HHS
ID : R56 NS036630
Pays : United States
Organisme : CIHR
Pays : Canada
Organisme : NINDS NIH HHS
ID : R01 NS036630
Pays : United States
Informations de copyright
© 2019 International Parkinson and Movement Disorder Society.
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