RT Journal Article
SR Electronic
T1 Novel Regulation of Parkin Function through c-Abl-Mediated Tyrosine Phosphorylation: Implications for Parkinson's Disease
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 157
OP 163
DO 10.1523/JNEUROSCI.1833-10.2011
VO 31
IS 1
A1 Syed Z. Imam
A1 Qing Zhou
A1 Ayako Yamamoto
A1 Anthony J. Valente
A1 Syed F. Ali
A1 Mona Bains
A1 James L. Roberts
A1 Philipp J. Kahle
A1 Robert A. Clark
A1 Senlin Li
YR 2011
UL http://www.jneurosci.org/content/31/1/157.abstract
AB 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.