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. 2019 Apr;34(4):526-535.
doi: 10.1002/mds.27642. Epub 2019 Feb 20.

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

Roy N Alcalay  1   2 , Victoria Mallett  3 , Benoît Vanderperre  4 , Omid Tavassoly  4 , Yves Dauvilliers  5 , Richard Y J Wu  3   6 , Jennifer A Ruskey  3   7 , Claire S Leblond  3   8 , Amirthagowri Ambalavanan  3   8 , Sandra B Laurent  3   7 , Dan Spiegelman  3   7 , Alexandre Dionne-Laporte  3   7 , Christopher Liong  1 , Oren A Levy  1 , Stanley Fahn  1 , Cheryl Waters  1 , Sheng-Han Kuo  1 , Wendy K Chung  9   10 , Blair Ford  1 , Karen S Marder  1 , Un Jung Kang  1 , Sharon Hassin-Baer  11   12   13 , Lior Greenbaum  11   14   15 , Jean-Francois Trempe  16 , Pavlina Wolf  17 , Petra Oliva  17 , Xiaokui Kate Zhang  17 , Lorraine N Clark  2   18   19 , Melanie Langlois  20   21 , Patrick A Dion  3   7 , Edward A Fon  4 , Nicolas Dupre  20   21 , Guy A Rouleau  3   7   8 , Ziv Gan-Or  3   7   8
Affiliations

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

Roy N Alcalay et al. Mov Disord. 2019 Apr.

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. © 2019 International Parkinson and Movement Disorder Society.

Keywords: SMPD1; Parkinson's disease; acid sphingomyelinase; genetics; α-synuclein.

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Conflict of interest statement

Conflict of interest disclosure: PW, PO and XKZ are employees of Sanofi. Sanofi is performing clinical trials targeting acid sphingomyelinase deficiency. RNA, ND and ZGO have received consultancy fees or research funding from Sanofi on topics not related to the current study. All other authors report no conflict of interests.

Figures

Figure 1.
Figure 1.. CRISPR/Cas9-mediated knockout of SMDP1 in Hela cells leads to α-synuclein accumulation.
(A) Twelve knockout clones were obtained using CRISPR/Cas9, and ASMase and α-synuclein expression were compared with wild-type cells by Western blotting. GAPDH was used as a loading control. Clones A6 and A8 (arrowheads) were further used for quantification. (B) Densitometric quantification of α-synuclein levels in clones A6 and A8 is shown. Data are mean ±SEM from 3 independent experiments. ** p<0.01, * p<0.05, paired t-test.
Figure 2.
Figure 2.. Some SMPD1 variants are associated with altered lysosomal localization of ASMase.
Hela cells were transfected with plasmids encoding variants of ASMase fused to a C-terminal Venus tag (green), and processed for immunofluorescence using an antibody against the lysosomal marker LAMP2 (magenta) before imaging using an epifluorescence microscope. Scale bar: 10 μm. The insets correspond to a zoom on the areas delineated by a dashed-square. ASMase with the p.L302P or p.P330fs mutations failed to reach the lysosomal compartment, and was almost exclusively localized in the endoplasmic reticulum. Trafficking of ASMase with the p.A487V variant seemed unaffected.
See this image and copyright information in PMC

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