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

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. alpha-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 alpha-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 alpha-synuclein accumulation. (c) 2019 International Parkinson and Movement Disorder Society.

  • Alcalay R N
  • Mallett V
  • Vanderperre B
  • Tavassoly O
  • Dauvilliers Y
  • Wu R Y J
  • Ruskey J A
  • Leblond C S
  • Ambalavanan A
  • Laurent S B
  • Spiegelman D
  • Dionne-Laporte A
  • Liong C
  • Levy O A
  • Fahn S
  • Waters C
  • Kuo S H
  • Chung W K
  • Ford B
  • Marder K S
  • Kang U J
  • Hassin-Baer S
  • Greenbaum L
  • Trempe J F
  • Wolf P
  • Oliva P
  • Zhang X K
  • Clark L N
  • Langlois M
  • Dion P A
  • Fon E A
  • Dupre N
  • Rouleau G A
  • Gan-Or Z


  • Mov Disord
Feb 20;Epub ahead of print():