RGD Reference Report - c-Abl phosphorylates alpha-synuclein and regulates its degradation: implication for alpha-synuclein clearance and contribution to the pathogenesis of Parkinson's disease. - Rat Genome Database

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c-Abl phosphorylates alpha-synuclein and regulates its degradation: implication for alpha-synuclein clearance and contribution to the pathogenesis of Parkinson's disease.

Authors: 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 
Citation: Mahul-Mellier AL, etal., Hum Mol Genet. 2014 Jun 1;23(11):2858-79. doi: 10.1093/hmg/ddt674. Epub 2014 Jan 9.
RGD ID: 8693592
Pubmed: PMID:24412932   (View Abstract at PubMed)
PMCID: PMC4014189   (View Article at PubMed Central)
DOI: DOI:10.1093/hmg/ddt674   (Journal Full-text)

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 alpha-synuclein (alpha-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 alpha-syn toxicity and clearance remain unknown. Herein, using NMR spectroscopy, mass spectrometry, in vitro enzymatic assays and cell-based studies, we established that alpha-syn is a bona fide substrate for c-Abl. In vitro studies demonstrate that c-Abl directly interacts with alpha-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 pY39 alpha-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 alpha-syn protein degradation via the autophagy and proteasome pathways, whereas the overexpression of alpha-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 alpha-syn clearance and contribute to the pathogenesis of PD.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Parkinson's disease  ISOAbl1 (Mus musculus)8693592; 8693592protein:increased expression:brain:RGD 
Parkinson's disease  ISOAbl1 (Rattus norvegicus)8693592; 8693592 RGD 
Parkinson's disease  IEP 8693592protein:increased expression:brain:RGD 
Parkinson's disease  IEP 8693592 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
neuronal cell body  IDA 8693592 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Abl1  (ABL proto-oncogene 1, non-receptor tyrosine kinase)

Genes (Mus musculus)
Abl1  (c-abl oncogene 1, non-receptor tyrosine kinase)

Genes (Homo sapiens)
ABL1  (ABL proto-oncogene 1, non-receptor tyrosine kinase)


Additional Information