C-Abl phosphorylates α-synuclein and regulates its degradation

Implication for α-synuclein clearance and contribution to the pathogenesis of parkinson's disease

Anne Laure Mahul-Mellier, Bruno Fauvet, Amanda Gysbers, Igor Dikiy, Abid Oueslati, Sandrine Georgeon, Allan J. Lamontanara, Alejandro Bisquertt, David Eliezer, Eliezer Masliah, Glenda Halliday, Oliver Hantschel, Hilal A. Lashuel

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Increasing evidence suggests that the c-Abl protein tyrosine kinase could play a role in the pathogenesis of Parkinson's disease (PD) and other neurodegenerative disorders. c-Abl has been shown to regulate the degradation of two proteins implicated in the pathogenesis of PD, parkin and a-synuclein (a-syn). The inhibition of parkin's neuroprotective functions is regulated by c-Abl-mediated phosphorylation of parkin. However, the molecular mechanisms by which c-Abl activity regulates a-syn toxicity and clearance remain unknown. Herein, using NMR spectroscopy, mass spectrometry, in vitro enzymatic assays and cell-based studies, we established thata-syn is a bona fide substrate for c-Abl. In vitro studiesdemonstrate that c-Abl directly interacts with a-syn and catalyzes its phosphorylation mainly at tyrosine 39 (pY39) and to a lesser extent at tyrosine 125 (pY125). Analysis of human brain tissues showed that pY39a-syn is detected in the brains of healthy individuals and those with PD. However, only c-Abl protein levels were found to be upregulated in PD brains. Interestingly, nilotinib, a specific inhibitor of c-Abl kinase activity, induces α-syn protein degradation via the autophagy and proteasome pathways, whereas the overexpression of a-syn in the rat midbrains enhances c-Abl expression. Together, these data suggest that changes in c-Abl expression, activation and/or c-Abl-mediated phosphorylation of Y39 play a role in regulating α-syn clearance and contribute to the pathogenesis of PD.

Original languageEnglish
Article numberddt674
Pages (from-to)2858-2879
Number of pages22
JournalHuman Molecular Genetics
Volume23
Issue number11
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes

Fingerprint

Synucleins
Parkinson Disease
Proto-Oncogene Proteins c-abl
Phosphorylation
Proteolysis
Tyrosine
Brain
Autophagy
Enzyme Assays
Proteasome Endopeptidase Complex
Mesencephalon
Neurodegenerative Diseases
Protein-Tyrosine Kinases
Mass Spectrometry
Phosphotransferases
Magnetic Resonance Spectroscopy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

C-Abl phosphorylates α-synuclein and regulates its degradation : Implication for α-synuclein clearance and contribution to the pathogenesis of parkinson's disease. / Mahul-Mellier, Anne Laure; Fauvet, Bruno; Gysbers, Amanda; Dikiy, Igor; Oueslati, Abid; Georgeon, Sandrine; Lamontanara, Allan J.; Bisquertt, Alejandro; Eliezer, David; Masliah, Eliezer; Halliday, Glenda; Hantschel, Oliver; Lashuel, Hilal A.

In: Human Molecular Genetics, Vol. 23, No. 11, ddt674, 01.01.2014, p. 2858-2879.

Research output: Contribution to journalArticle

Mahul-Mellier, AL, Fauvet, B, Gysbers, A, Dikiy, I, Oueslati, A, Georgeon, S, Lamontanara, AJ, Bisquertt, A, Eliezer, D, Masliah, E, Halliday, G, Hantschel, O & Lashuel, HA 2014, 'C-Abl phosphorylates α-synuclein and regulates its degradation: Implication for α-synuclein clearance and contribution to the pathogenesis of parkinson's disease', Human Molecular Genetics, vol. 23, no. 11, ddt674, pp. 2858-2879. https://doi.org/10.1093/hmg/ddt674
Mahul-Mellier, Anne Laure ; Fauvet, Bruno ; Gysbers, Amanda ; Dikiy, Igor ; Oueslati, Abid ; Georgeon, Sandrine ; Lamontanara, Allan J. ; Bisquertt, Alejandro ; Eliezer, David ; Masliah, Eliezer ; Halliday, Glenda ; Hantschel, Oliver ; Lashuel, Hilal A. / C-Abl phosphorylates α-synuclein and regulates its degradation : Implication for α-synuclein clearance and contribution to the pathogenesis of parkinson's disease. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 11. pp. 2858-2879.
@article{cffd76bd8cbe423c8161ea8083516b11,
title = "C-Abl phosphorylates α-synuclein and regulates its degradation: Implication for α-synuclein clearance and contribution to the pathogenesis of parkinson's disease",
abstract = "Increasing evidence suggests that the c-Abl protein tyrosine kinase could play a role in the pathogenesis of Parkinson's disease (PD) and other neurodegenerative disorders. c-Abl has been shown to regulate the degradation of two proteins implicated in the pathogenesis of PD, parkin and a-synuclein (a-syn). The inhibition of parkin's neuroprotective functions is regulated by c-Abl-mediated phosphorylation of parkin. However, the molecular mechanisms by which c-Abl activity regulates a-syn toxicity and clearance remain unknown. Herein, using NMR spectroscopy, mass spectrometry, in vitro enzymatic assays and cell-based studies, we established thata-syn is a bona fide substrate for c-Abl. In vitro studiesdemonstrate that c-Abl directly interacts with a-syn and catalyzes its phosphorylation mainly at tyrosine 39 (pY39) and to a lesser extent at tyrosine 125 (pY125). Analysis of human brain tissues showed that pY39a-syn is detected in the brains of healthy individuals and those with PD. However, only c-Abl protein levels were found to be upregulated in PD brains. Interestingly, nilotinib, a specific inhibitor of c-Abl kinase activity, induces α-syn protein degradation via the autophagy and proteasome pathways, whereas the overexpression of a-syn in the rat midbrains enhances c-Abl expression. Together, these data suggest that changes in c-Abl expression, activation and/or c-Abl-mediated phosphorylation of Y39 play a role in regulating α-syn clearance and contribute to the pathogenesis of PD.",
author = "Mahul-Mellier, {Anne Laure} and Bruno Fauvet and Amanda Gysbers and Igor Dikiy and Abid Oueslati and Sandrine Georgeon and Lamontanara, {Allan J.} and Alejandro Bisquertt and David Eliezer and Eliezer Masliah and Glenda Halliday and Oliver Hantschel and Lashuel, {Hilal A.}",
year = "2014",
month = "1",
day = "1",
doi = "10.1093/hmg/ddt674",
language = "English",
volume = "23",
pages = "2858--2879",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "11",

}

TY - JOUR

T1 - C-Abl phosphorylates α-synuclein and regulates its degradation

T2 - Implication for α-synuclein clearance and contribution to the pathogenesis of parkinson's disease

AU - Mahul-Mellier, Anne Laure

AU - Fauvet, Bruno

AU - Gysbers, Amanda

AU - Dikiy, Igor

AU - Oueslati, Abid

AU - Georgeon, Sandrine

AU - Lamontanara, Allan J.

AU - Bisquertt, Alejandro

AU - Eliezer, David

AU - Masliah, Eliezer

AU - Halliday, Glenda

AU - Hantschel, Oliver

AU - Lashuel, Hilal A.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Increasing evidence suggests that the c-Abl protein tyrosine kinase could play a role in the pathogenesis of Parkinson's disease (PD) and other neurodegenerative disorders. c-Abl has been shown to regulate the degradation of two proteins implicated in the pathogenesis of PD, parkin and a-synuclein (a-syn). The inhibition of parkin's neuroprotective functions is regulated by c-Abl-mediated phosphorylation of parkin. However, the molecular mechanisms by which c-Abl activity regulates a-syn toxicity and clearance remain unknown. Herein, using NMR spectroscopy, mass spectrometry, in vitro enzymatic assays and cell-based studies, we established thata-syn is a bona fide substrate for c-Abl. In vitro studiesdemonstrate that c-Abl directly interacts with a-syn and catalyzes its phosphorylation mainly at tyrosine 39 (pY39) and to a lesser extent at tyrosine 125 (pY125). Analysis of human brain tissues showed that pY39a-syn is detected in the brains of healthy individuals and those with PD. However, only c-Abl protein levels were found to be upregulated in PD brains. Interestingly, nilotinib, a specific inhibitor of c-Abl kinase activity, induces α-syn protein degradation via the autophagy and proteasome pathways, whereas the overexpression of a-syn in the rat midbrains enhances c-Abl expression. Together, these data suggest that changes in c-Abl expression, activation and/or c-Abl-mediated phosphorylation of Y39 play a role in regulating α-syn clearance and contribute to the pathogenesis of PD.

AB - Increasing evidence suggests that the c-Abl protein tyrosine kinase could play a role in the pathogenesis of Parkinson's disease (PD) and other neurodegenerative disorders. c-Abl has been shown to regulate the degradation of two proteins implicated in the pathogenesis of PD, parkin and a-synuclein (a-syn). The inhibition of parkin's neuroprotective functions is regulated by c-Abl-mediated phosphorylation of parkin. However, the molecular mechanisms by which c-Abl activity regulates a-syn toxicity and clearance remain unknown. Herein, using NMR spectroscopy, mass spectrometry, in vitro enzymatic assays and cell-based studies, we established thata-syn is a bona fide substrate for c-Abl. In vitro studiesdemonstrate that c-Abl directly interacts with a-syn and catalyzes its phosphorylation mainly at tyrosine 39 (pY39) and to a lesser extent at tyrosine 125 (pY125). Analysis of human brain tissues showed that pY39a-syn is detected in the brains of healthy individuals and those with PD. However, only c-Abl protein levels were found to be upregulated in PD brains. Interestingly, nilotinib, a specific inhibitor of c-Abl kinase activity, induces α-syn protein degradation via the autophagy and proteasome pathways, whereas the overexpression of a-syn in the rat midbrains enhances c-Abl expression. Together, these data suggest that changes in c-Abl expression, activation and/or c-Abl-mediated phosphorylation of Y39 play a role in regulating α-syn clearance and contribute to the pathogenesis of PD.

UR - http://www.scopus.com/inward/record.url?scp=84899894003&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899894003&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddt674

DO - 10.1093/hmg/ddt674

M3 - Article

VL - 23

SP - 2858

EP - 2879

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 11

M1 - ddt674

ER -