Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson's disease
Authors: Anthony J Valente
Syed F Ali
Syed Z Imam
Qing Zhou
Robert A Clark
Philipp J Kahle
Ayako Yamamoto
James L Roberts
Mona Bains
Senlin Li
Journal: Journal of Neuroscience (2011)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Parkin; c-Abl; Parkinson's disease; tyrosine phosphorylation; E3 ubiquitin ligase
Affiliations: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229, USA. 

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. 

Retracted: No

PubPeer comments:
 Concerns about Figure 1C. Image made a bit darker to bring out details. * Boxes of the same color highlight areas within the same photo that look quite similar. * Orange arrow: The ~30 kDa band in the left lane is surrounded by sharp background transitions. Could the authors please show the original uncropped blot or film? ![file] , 
 Concerns about Figure 1B. Image made a bit darker to bring out details. * Boxes of the same color highlight areas within the same photo that look quite similar. * Orange arrows: Several lanes appear to be separated from each other by sharp vertical background transitions. ![file] , 
 Concerns about Figure 1D. Image made a bit darker to bring out details. * Boxes of the same color highlight areas within the same photo that look quite similar. * Orange arrows: Sharp background transitions. ![file] , 
 Concerns about Figure 1E. Image made a bit darker to bring out details. * Boxes of the same color highlight areas within the same photo that look quite similar. * Orange arrows: Sharp background transitions. ![file] , 
 Concerns about Figure 2A. * Green boxes: bands within the same photo that look quite similar. * Note that the whole IB:Actin panel looks remarkably similar to the GST-SH2-TK band in Figure 1D (see comment #3) * Orange arrows: Sharp background transition. ![file] , 
 Concerns about Figure 2F. * Boxes of the same color highlight areas within the same photo that look quite similar. * Orange arrows: Sharp background transitions. ![file] ,