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 L.; Kahle, Philipp J.; Clark, Robert A.; Li, Senlin

doi:10.1523/jneurosci.1833-10.2011

Cited by 183 publications

(213 citation statements)

References 31 publications

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“…It has been reported that c-Abl mediates PD pathogenesis via targets such as parkin and α-synuclein. 9,10,16 However, the molecular mechanisms by which c-Abl participates in oxidative stress-induced PD remain unknown. Because c-Abl is a tyrosine kinase, its substrates can be determined via SILAC technology followed by the identification of the tyrosine-phosphorylated peptides.…”

Section: Resultsmentioning

confidence: 99%

“…25 Recently, extensive studies have been performed on c-Abl in the nervous system to investigate its role in neurodegenerative disease. [9][10][11][12][13][14]26 For example, c-Abl kinase has been reported to regulate the accumulation of AIMP2 (aminoacyl tRNA synthetase complex-interacting multifunctional protein 2), FBP1 (far upstream elementbinding protein 1), and α-synuclein in PD models. 9,10,11 Here, by using the SILAC analysis, we identified p38α as a major Figure 6 The p38α inhibitor SB203580 protects against MPTP-induced dopaminergic neuronal death and motor deficits.…”

Section: Discussionmentioning

confidence: 99%

“…5 Our group and other groups have reported that c-Abl plays an important role in oxidative stress-induced neuronal death. 6-8 Recently, Ko et al 9 and Imam et al 10 have reported that c-Abl phosphorylated Parkin and inhibited its E3 ligase activity that led to the neurotoxic accumulation of Parkin's substrates. α-Synuclein has also been reported to be substrates of c-Abl and to participate in PD pathogenesis.…”

mentioning

confidence: 99%

“…α-Synuclein has also been reported to be substrates of c-Abl and to participate in PD pathogenesis. [9][10][11] The c-Abl inhibitor Nilotinib and INNO-406 have been reported prevents the loss of dopamine neurons and improves motor behavior in a murine PD model. [12][13][14] In this study, we demonstrated that c-Abl is activated in oxidative stress-induced PD.…”

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c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

Chen

et al. 2015

Cell Death Differ

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Oxidative stress is a major cause of sporadic Parkinson's disease (PD). Here, we demonstrated that c-Abl plays an important role in oxidative stress-induced neuronal cell death. C-Abl, a nonreceptor tyrosine kinase, was activated in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced acute PD model. Conditional knockout of c-Abl in neurons or treatment of mice with STI571, a c-Abl family kinase inhibitor, reduced the loss of dopaminergic neurons and ameliorated the locomotive defects induced by short-term MPTP treatment. By combining the SILAC (stable isotope labeling with amino acids in cell culture) technique with other biochemical methods, we identified p38α as a major substrate of c-Abl both in vitro and in vivo and c-Ablmediated phosphorylation is critical for the dimerization of p38α. Furthermore, p38α inhibition mitigated the MPTP-induced loss of dopaminergic neurons. Taken together, these data suggested that c-Abl-p38α signaling may represent a therapeutic target for PD. Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by bradykinesia, rigidity, tremor, and loss of dopaminergic neurons. 1 Familial mutations that cause PD have been identified, including in the genes that encode α-synuclein and leucine-rich repeat kinase 2 (LRRK2) that cause autosomal-dominant PD, and DJ-1, PINK1, and parkin that cause autosomal-recessive PD. 2 However, the majority of PD cases are sporadic. The cause of sporadic PD remains unknown, and the role of environmental toxins and genetic factors in sporadic PD is unclear. However, the evidence regarding postencephalitic PD and the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced Parkinsonism suggest that environmental toxins may be a major cause of sporadic PD. 3,4 The neurotoxins used to induce dopaminergic neurodegeneration, including 6-hydroxydopamine, MPTP, and rotenone, induce the formation of reactive oxygen species (ROS). ROS react with nucleic acids, proteins, and lipids to induce mitochondrial damage. Although oxidative stress plays a critical role in causing PD, the mechanisms underlying oxidative stress-induced PD remain unclear.The nonreceptor tyrosine kinase c-Abl is ubiquitously expressed and mediates a variety of extrinsic and intrinsic cell signaling activities, including growth factor signaling, cell adhesion, oxidative stress, and DNA damage. 5 Our group and other groups have reported that c-Abl plays an important role in oxidative stress-induced neuronal death. 6-8 Recently, Ko et al. 9 and Imam et al. 10 have reported that c-Abl phosphorylated Parkin and inhibited its E3 ligase activity that led to the neurotoxic accumulation of Parkin's substrates. α-Synuclein has also been reported to be substrates of c-Abl and to participate in PD pathogenesis. 9-11 The c-Abl inhibitor Nilotinib and INNO-406 have been reported prevents the loss of dopamine neurons and improves motor behavior in a murine PD model. [12][13][14] In this study, we demonstrated that c-Abl ...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

Chen

et al. 2015

Cell Death Differ

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“…However, proteasomal degradation by parkin-mediated Lys-48-linked substrate polyubiquitination has been the most extensively studied function of parkin. In particular, AIPM2 (aminoacyl-tRNA synthetase-interacting multifunctional protein type 2; p38/JTV-1) (15), FBP1 (fuse-binding protein 1) (16), and PARIS (17) have been found to accumulate in parkin knock-out mice, suggesting that parkin-mediated ubiquitination is required for their targeting to the 26 S proteasome for degradation. Recently, parkin activity has been associated with the clearance of depolarized mitochondria by mitophagy (18), where parkin recruitment to mitochondria and its ubiquitin ligase activity are controlled by PINK1 (PTENinduced putative kinase 1) phosphorylation of both parkin and Ub (19 -21).…”

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confidence: 99%

The E3 Ubiquitin Ligase Parkin Is Recruited to the 26 S Proteasome via the Proteasomal Ubiquitin Receptor Rpn13

Aguileta

Korać

Durcan

et al. 2015

Journal of Biological Chemistry

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Background:The role of the N-terminal ubiquitin-like domain of the E3 ligase parkin is not fully understood. Results: Parkin is recruited to the 26 S proteasome through the interaction of its ubiquitin-like domain with the intrinsic proteasomal ubiquitin receptor Rpn13. Conclusion: Parkin turnover and E3 ligase activity can be regulated by its recruitment to the 26 S proteasome via Rpn13. Significance: Parkin-Rpn13 interaction might be exploited as a potential therapeutic strategy.

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