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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Brain / metabolism*
  • Brain / pathology
  • Female
  • Gene Knockdown Techniques
  • Genetic Predisposition to Disease*
  • HeLa Cells
  • Humans
  • Jews / genetics
  • Male
  • Middle Aged
  • Mutation
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Sphingomyelin Phosphodiesterase / genetics*
  • alpha-Synuclein / metabolism*


  • alpha-Synuclein
  • SMPD1 protein, human
  • Sphingomyelin Phosphodiesterase