Session Information
Date: Tuesday, June 21, 2016
Session Title: Parkinson's disease: Genetics
Session Time: 12:30pm-2:00pm
Location: Exhibit Hall located in Hall B, Level 2
Objective: To study the effects of SMPD1 (sphingomyelin phosphodiesterase-1 gene) variants and acid-sphingomyelinase (ASMase) activity on Parkinson’s disease (PD), and the effect of SMPD1 knockdown on α-synuclein accumulation.
Background: In recent years, SMPD1 variants were associated with PD and synucleinopathies in several populations. However, more studies are needed to elucidate the role of SMPD1 in PD.
Methods: SMPD1 was sequenced in two cohorts from New-York and Montreal/Montpellier, with a total of 1075 PD patients and 975 controls. The activity of acid sphingomyelinase (ASMase) was measured in 550 patients and 284 controls (from the New-York cohort) by a mass-spectrometry-based assay in dried blood spots. Two cellular models (HeLa cells and BE(2)-M17 cells) were used for SiRNA SMPD1 knockdown, and α-synuclein quantity was estimated.
Results: SMPD1 variants were more common in PD (n=525) versus controls (n=691) in the Montreal/Montpellier cohort (5.3% versus 2.9%, p=0.037), but this association was driven by a single variant, p.A487V (1.5% versus 0.14%, p=0.0065). This variant was found in additional three patients and one control in the New-York cohort (combined frequency 1.0% vs. 0.2%, OR=5.03, 95%CI=1.11-22.75, p=0.024). There was no significant difference in ASMase activity comparing PD and control in the New-York cohort (4.64 ± 1.68 versus 4.62 ± 1.64, p=0.84). Interestingly, among PD patients, reduced ASMase activity was associated with an earlier age–at-onset of PD, with 3.5-5.8 years earlier onset in the lowest quartile vs. the highest quartile of ASMase activity (p=0.01-0.001 in all comparisons). Knockdown of SMPD1 resulted in increase of α-synuclein in both HeLa cells and BE(2)-M17 cells.
Conclusions: Our results support an association between SMPD1 and its product ASMase with PD risk and phenotype, possibly because of α-synuclein accumulation in presence of low ASMase activity. Further genetic and functional studies are necessary to better elucidate the role of SMPD1 in PD and other synucleinopathies.
To cite this abstract in AMA style:
Z. Gan-Or, V. Mallett, O. Tavassoly, Y. Dauvilliers, C. Leblond, A. Ambalavanan, S. Laurent, S. Strong, D. Spiegelman, A. Dionne-Laporte, C. Liong, O. Levy, S. Fahn, C. Waters, P. Mazzoni, S. Kuo, W. Chung, B. Ford, K. Marder, U. Kang, P. Wolf, P. Oliva, X. Zhang, L. Clark, P. Dion, E. Fon, N. Dupre, G. Rouleau, R. Alcalay. SMPD1 mutations, acid-sphingomyelinase activity and α-synuclein accumulation in Parkinson’s disease [abstract]. Mov Disord. 2016; 31 (suppl 2). https://www.mdsabstracts.org/abstract/smpd1-mutations-acid-sphingomyelinase-activity-and-synuclein-accumulation-in-parkinsons-disease/. Accessed May 10, 2025.« Back to 2016 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/smpd1-mutations-acid-sphingomyelinase-activity-and-synuclein-accumulation-in-parkinsons-disease/