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

Roy N. Alcalay, Victoria Mallett, Benoît Vanderperre, Omid Tavassoly, Yves Dauvilliers, Richard Y.J. Wu, Jennifer A. Ruskey, Claire S. Leblond, Amirthagowri Ambalavanan, Sandra B. Laurent, Dan Spiegelman, Alexandre Dionne-Laporte, Christopher Liong, Oren A. Levy, Stanley Fahn, Cheryl Waters, Sheng Han Kuo, Wendy K. Chung, Blair Ford, Karen S. MarderUn Jung Kang, Sharon Hassin-Baer, Lior Greenbaum, Jean Francois Trempe, Pavlina Wolf, Petra Oliva, Xiaokui Kate Zhang, Lorraine N. Clark, Melanie Langlois, Patrick A. Dion, Edward A. Fon, Nicolas Dupre, Guy A. Rouleau, Ziv Gan-Or

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)526-535
Number of pages10
JournalMovement Disorders
Volume34
Issue number4
DOIs
StatePublished - Apr 2019
Externally publishedYes

Fingerprint

Synucleins
Sphingomyelin Phosphodiesterase
Parkinson Disease
Mutation
Acids
Clustered Regularly Interspaced Short Palindromic Repeats
Israel
Lysosomes
Computer Simulation
Small Interfering RNA
Mass Spectrometry

Keywords

  • Parkinson's disease
  • SMPD1
  • acid sphingomyelinase
  • genetics
  • α-synuclein

Cite this

Alcalay, R. N., Mallett, V., Vanderperre, B., Tavassoly, O., Dauvilliers, Y., Wu, R. Y. J., ... Gan-Or, Z. (2019). SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease. Movement Disorders, 34(4), 526-535. https://doi.org/10.1002/mds.27642
Alcalay, Roy N. ; Mallett, Victoria ; Vanderperre, Benoît ; Tavassoly, Omid ; Dauvilliers, Yves ; Wu, Richard Y.J. ; Ruskey, Jennifer A. ; Leblond, Claire S. ; Ambalavanan, Amirthagowri ; Laurent, Sandra B. ; Spiegelman, Dan ; Dionne-Laporte, Alexandre ; Liong, Christopher ; Levy, Oren A. ; Fahn, Stanley ; Waters, Cheryl ; Kuo, Sheng Han ; Chung, Wendy K. ; Ford, Blair ; Marder, Karen S. ; Kang, Un Jung ; Hassin-Baer, Sharon ; Greenbaum, Lior ; Trempe, Jean Francois ; Wolf, Pavlina ; Oliva, Petra ; Zhang, Xiaokui Kate ; Clark, Lorraine N. ; Langlois, Melanie ; Dion, Patrick A. ; Fon, Edward A. ; Dupre, Nicolas ; Rouleau, Guy A. ; Gan-Or, Ziv. / SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease. In: Movement Disorders. 2019 ; Vol. 34, No. 4. pp. 526-535.
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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.",
keywords = "Parkinson's disease, SMPD1, acid sphingomyelinase, genetics, α-synuclein",
author = "Alcalay, {Roy N.} and Victoria Mallett and Beno{\^i}t Vanderperre and Omid Tavassoly and Yves Dauvilliers and Wu, {Richard Y.J.} and Ruskey, {Jennifer A.} and Leblond, {Claire S.} and Amirthagowri Ambalavanan and Laurent, {Sandra B.} and Dan Spiegelman and Alexandre Dionne-Laporte and Christopher Liong and Levy, {Oren A.} and Stanley Fahn and Cheryl Waters and Kuo, {Sheng Han} and Chung, {Wendy K.} and Blair Ford and Marder, {Karen S.} and Kang, {Un Jung} and Sharon Hassin-Baer and Lior Greenbaum and Trempe, {Jean Francois} and Pavlina Wolf and Petra Oliva and Zhang, {Xiaokui Kate} and Clark, {Lorraine N.} and Melanie Langlois and Dion, {Patrick A.} and Fon, {Edward A.} and Nicolas Dupre and Rouleau, {Guy A.} and Ziv Gan-Or",
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Alcalay, RN, Mallett, V, Vanderperre, B, Tavassoly, O, Dauvilliers, Y, Wu, RYJ, Ruskey, JA, Leblond, CS, Ambalavanan, A, Laurent, SB, Spiegelman, D, Dionne-Laporte, A, Liong, C, Levy, OA, Fahn, S, Waters, C, Kuo, SH, Chung, WK, Ford, B, Marder, KS, Kang, UJ, Hassin-Baer, S, Greenbaum, L, Trempe, JF, Wolf, P, Oliva, P, Zhang, XK, Clark, LN, Langlois, M, Dion, PA, Fon, EA, Dupre, N, Rouleau, GA & Gan-Or, Z 2019, 'SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease', Movement Disorders, vol. 34, no. 4, pp. 526-535. https://doi.org/10.1002/mds.27642

SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease. / Alcalay, Roy N.; Mallett, Victoria; Vanderperre, Benoît; Tavassoly, Omid; Dauvilliers, Yves; Wu, Richard Y.J.; Ruskey, Jennifer A.; Leblond, Claire S.; Ambalavanan, Amirthagowri; Laurent, Sandra B.; Spiegelman, Dan; Dionne-Laporte, Alexandre; Liong, Christopher; Levy, Oren A.; Fahn, Stanley; Waters, Cheryl; Kuo, Sheng Han; Chung, Wendy K.; Ford, Blair; Marder, Karen S.; Kang, Un Jung; Hassin-Baer, Sharon; Greenbaum, Lior; Trempe, Jean Francois; Wolf, Pavlina; Oliva, Petra; Zhang, Xiaokui Kate; Clark, Lorraine N.; Langlois, Melanie; Dion, Patrick A.; Fon, Edward A.; Dupre, Nicolas; Rouleau, Guy A.; Gan-Or, Ziv.

In: Movement Disorders, Vol. 34, No. 4, 04.2019, p. 526-535.

Research output: Contribution to journalArticle

TY - JOUR

T1 - SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease

AU - Alcalay, Roy N.

AU - Mallett, Victoria

AU - Vanderperre, Benoît

AU - Tavassoly, Omid

AU - Dauvilliers, Yves

AU - Wu, Richard Y.J.

AU - Ruskey, Jennifer A.

AU - Leblond, Claire S.

AU - Ambalavanan, Amirthagowri

AU - Laurent, Sandra B.

AU - Spiegelman, Dan

AU - Dionne-Laporte, Alexandre

AU - Liong, Christopher

AU - Levy, Oren A.

AU - Fahn, Stanley

AU - Waters, Cheryl

AU - Kuo, Sheng Han

AU - Chung, Wendy K.

AU - Ford, Blair

AU - Marder, Karen S.

AU - Kang, Un Jung

AU - Hassin-Baer, Sharon

AU - Greenbaum, Lior

AU - Trempe, Jean Francois

AU - Wolf, Pavlina

AU - Oliva, Petra

AU - Zhang, Xiaokui Kate

AU - Clark, Lorraine N.

AU - Langlois, Melanie

AU - Dion, Patrick A.

AU - Fon, Edward A.

AU - Dupre, Nicolas

AU - Rouleau, Guy A.

AU - Gan-Or, Ziv

PY - 2019/4

Y1 - 2019/4

N2 - 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.

AB - 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.

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KW - SMPD1

KW - acid sphingomyelinase

KW - genetics

KW - α-synuclein

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U2 - 10.1002/mds.27642

DO - 10.1002/mds.27642

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Alcalay RN, Mallett V, Vanderperre B, Tavassoly O, Dauvilliers Y, Wu RYJ et al. SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease. Movement Disorders. 2019 Apr;34(4):526-535. https://doi.org/10.1002/mds.27642