Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson’s disease
Open accessAbstract
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.
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c-Abl is one of the factors involved in neurodegenerative diseases.
“Accumulating evidence indicate that c-Abl is one of the factors involved in neurodegenerative diseases”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Imam et al., 2011
c-Abl has been identified as an important pathogenic mediator of neurodegenerative diseases.
“Since c-Abl has been identified as an important pathogenic mediator of neurodegenerative diseases (Alvarez et al., 2004; Imam et al., 2011; Jing et al., 2009; Ko et al., 2010; Schlatterer et al., 2011)”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Imam et al., 2011
Alterations in c-Abl activity play a central role in several neurodegenerative diseases, including PD and AD.
“Indeed, emerging evidence shows that alterations in c-Abl ac tivity play a central role in several neurodegenerative diseases, including PD and AD (Gonfloni et al., 2012; Hebron et al., 2013a; Imam et al., 2011; Jing et al., 2009; Karuppagounder et al., 2014; Ko et al., 2010; Lindholm et al., 2016; Schlatterer et al., 2011).”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Imam et al., 2011
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- Authors
- Imam, S. Z., Zhou, Q., Yamamoto, A., Valente, A. J., Ali, S. F., Bains, M., Roberts, J. L., Kahle, P. J., Clark, R. A., & Li, S.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Harvard University (US)
- Hertie Institute for Clinical Brain Research (DE)
- National Institutes of Health (US)
- National Center for Toxicological Research (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-01-05
- Volume
- 31
- Issue
- 1
- Pages
- 157-163
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3039694
- OpenAlex
- W1996577359
- Cited by
- 214
- References
- 31
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 15 · 2023: 13 · 2022: 18 · 2021: 18 · 2020: 19 · 2019: 15 · 2018: 10 · 2017: 15 · 2016: 15 · 2015: 8 · 2014: 13 · 2013: 18 · 2012: 8
- FWCI
- 8.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- Parkinson's Disease Foundation
- San Antonio Area Foundation
- American Parkinson Disease Association
- European Commission
- National Institutes of Health
- University of Texas Health Science Center at San Antonio
- National Institute of Neurological Disorders and Stroke (R01NS046004)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Parkin, c-Abl, tyrosine phosphorylation, Parkinson's disease, E3 ubiquitin ligase, non-receptor tyrosine kinase, oxidative stress, striatum, AIMP2, post-translational modification
- MeSH terms
- Imatinib Mesylate, Acetylcysteine, Animals, Benzamides, Brain, Cell Line, Disease Models, Animal, Dopamine, Drug Administration Schedule, Gene Expression Regulation, Humans, Male, Metalloporphyrins, Mice, Inbred C57BL, Peptide Elongation Factors, Phosphorylation, Piperazines, Polyethylene Glycols, Pyrimidines, Transfection, Tyrosine, Case-Control Studies, Free Radical Scavengers, Proto-Oncogene Proteins c-abl, Oxidative Stress, Statistics, Nonparametric, MPTP Poisoning, Tumor Suppressor Proteins, RNA, Small Interfering, Ubiquitin-Protein Ligases, Protein Kinase Inhibitors, Immunoprecipitation, Green Fluorescent Proteins, Mice, Ubiquitination
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