Han Seok Koa,b, Yunjong Leea,c Joo-Ho Shina,b, Senthilkumar S. Karuppagoundera,b, Bharathi Shrikanth Gadada,b, Anthony J. Kolesked, Olga Pletnikovae, Juan C. Troncosob,e, Valina L. Dawsona,b,c,f, and Ted M. Dawsona,b,f,1
aNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering,
Departments of bNeurology,
ePathology, Division of Neuropathology, and
fSolomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and
dDepartment of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520
Edited* by Ann M. Graybiel, Massachusetts Institute of Technology, Cambridge, MA, and approved August 11, 2010 (received for review May 7, 2010)
Mutations in PARK2/Parkin, which encodes a ubiquitin E3 ligase, cause autosomal recessive Parkinson disease (PD). Here we show that the nonreceptor tyrosine kinase c-Abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin E3 ligase activity and protective function. c-Abl is activated by dopaminergic stress and by dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) in vitro and in vivo by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), leading to parkin inactivation, accumulation of the parkin substrates aminoacyl-tRNA synthetase-interacting multifunctional protein type 2 (AIMP2) (p38/JTV-1) and fuse-binding protein 1 (FBP1), and cell death. STI-571, a c-Abl-family kinase inhibitor, prevents the phosphorylation of parkin, maintaining parkin in a catalytically active and protective state. STI-571’s protective effects require parkin, as shRNA knockdown of parkin prevents STI-571 protection. Conditional knockout of c-Abl in the nervous system also prevents the phosphorylation of parkin, the accumulation of its substrates, and subsequent neurotoxicity in response to MPTP intoxication. In human postmortem PD brain, c-Abl is active, parkin is tyrosine-phosphorylated, and AIMP2 and FBP1 accumulate in the substantia nigra and striatum. Thus, tyrosine phosphorylation of parkin by c-Abl is a major posttranslational modification that inhibits parkin function, possibly contributing to pathogenesis of sporadic PD. Moreover, inhibition of c-Abl may be a neuroprotective approach in the treatment of PD.
AIMP2, Parkinson disease, STI-571, ubiquitin
1To whom correspondence should be addressed.
Author contributions: H.S.K., V.L.D., and T.M.D. designed research; H.S.K., Y.L., J.-H.S., S.S.K., and B.S.G. performed research; A.J.K., O.P., and J.C.T. contributed new reagents/analytic tools; H.S.K., Y.L., J.-H.S., S.S.K., V.L.D., and T.M.D. analyzed data; and H.S.K., V.L.D., and T.M.D. wrote the paper.
The authors declare no conflict of interest.
*This Direct Submission article had a prearranged editor.
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