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 Roberts, Philipp J. Kahle, Robert A Clark, Senlin Li

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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

Fingerprint

Parkinson Disease
Tyrosine
Phosphorylation
Ubiquitin-Protein Ligases
Disease Progression
Amino Acyl-tRNA Synthetases
Post Translational Protein Processing
Ligases
Ubiquitin
Inbred C57BL Mouse
Protein-Tyrosine Kinases
Cultured Cells
Oxidative Stress
Mutation
Proteins
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Novel regulation of Parkin function through c-Abl-mediated tyrosine phosphorylation : Implications for Parkinson's disease. / Imam, Syed Z.; Zhou, Qing; Yamamoto, Ayako; Valente, Anthony J.; Ali, Syed F.; Bains, Mona; Roberts, James; Kahle, Philipp J.; Clark, Robert A; Li, Senlin.

In: Journal of Neuroscience, Vol. 31, No. 1, 05.01.2011, p. 157-163.

Research output: Contribution to journalArticle

Imam, SZ, Zhou, Q, Yamamoto, A, Valente, AJ, Ali, SF, Bains, M, Roberts, J, Kahle, PJ, Clark, RA & Li, S 2011, 'Novel regulation of Parkin function through c-Abl-mediated tyrosine phosphorylation: Implications for Parkinson's disease', Journal of Neuroscience, vol. 31, no. 1, pp. 157-163. https://doi.org/10.1523/JNEUROSCI.1833-10.2011
Imam, Syed Z. ; Zhou, Qing ; Yamamoto, Ayako ; Valente, Anthony J. ; Ali, Syed F. ; Bains, Mona ; Roberts, James ; Kahle, Philipp J. ; Clark, Robert A ; Li, Senlin. / Novel regulation of Parkin function through c-Abl-mediated tyrosine phosphorylation : Implications for Parkinson's disease. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 1. pp. 157-163.
@article{7639378a27ea47fd8d2b13cee8ec4eaa,
title = "Novel regulation of Parkin function through c-Abl-mediated tyrosine phosphorylation: Implications for Parkinson's disease",
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",
author = "Imam, {Syed Z.} and Qing Zhou and Ayako Yamamoto and Valente, {Anthony J.} and Ali, {Syed F.} and Mona Bains and James Roberts and Kahle, {Philipp J.} and Clark, {Robert A} and Senlin Li",
year = "2011",
month = "1",
day = "5",
doi = "10.1523/JNEUROSCI.1833-10.2011",
language = "English",
volume = "31",
pages = "157--163",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "1",

}

TY - JOUR

T1 - Novel regulation of Parkin function through c-Abl-mediated tyrosine phosphorylation

T2 - Implications for Parkinson's disease

AU - Imam, Syed Z.

AU - Zhou, Qing

AU - Yamamoto, Ayako

AU - Valente, Anthony J.

AU - Ali, Syed F.

AU - Bains, Mona

AU - Roberts, James

AU - Kahle, Philipp J.

AU - Clark, Robert A

AU - Li, Senlin

PY - 2011/1/5

Y1 - 2011/1/5

N2 - 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

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. Copyright

UR - http://www.scopus.com/inward/record.url?scp=78650881155&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650881155&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.1833-10.2011

DO - 10.1523/JNEUROSCI.1833-10.2011

M3 - Article

VL - 31

SP - 157

EP - 163

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 1

ER -