Novel regulation of Parkin function through c-Abl-mediated tyrosine phosphorylation: Implications for Parkinson's disease

Syed Z. Imam, Qing Zhou, Ayako Yamamoto, Anthony J. Valente, Syed F. Ali, Mona Bains, James L. Roberts, Philipp J. Kahle, Robert A. Clark, Senlin Li

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

Abstract

Mutations in parkin, an E3 ubiquitin ligase, are the most common cause of autosomal-recessive Parkinson's disease (PD). Here, we show that the stress-signaling non-receptor tyrosine kinase c-Abl links parkin to sporadic forms of PD via tyrosine phosphorylation. Under oxidative and dopaminergic stress, c-Abl was activated in cultured neuronal cells and in striatum of adult C57BL/6 mice. Activated c-Abl was found in the striatum of PD patients. Concomitantly, parkin was tyrosine-phosphorylated, causing loss of its ubiquitin ligase and cytoprotective activities, and the accumulation of parkin substrates, AIMP2 (aminoacyl tRNA synthetase complex-interacting multifunctional protein 2) (p38/JTV-1) and FBP-1.STI-571, a selective c-Abl inhibitor, prevented tyrosine phosphorylation of parkin and restored its E3 ligase activity and cytoprotective function both in vitro and in vivo. Our results suggest that tyrosine phosphorylation of parkin by c-Abl is a major post-translational modification that leads to loss of parkin function and disease progression in sporadic PD. Moreover, inhibition of c-Abl offers new therapeutic opportunities for blocking PD progression. Copyright

Original languageEnglish (US)
Pages (from-to)157-163
Number of pages7
JournalJournal of Neuroscience
Volume31
Issue number1
DOIs
StatePublished - Jan 5 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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