期刊
BRAIN
卷 142, 期 -, 页码 2380-2401出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awz172
关键词
zinc finger protein 746; PARIS; alpha-synuclein; parkin; Parkinson's disease
资金
- NIH/NINDS Morris K. Udall Parkinson's Disease Research Center [NS38377]
- NIH/NINDS [NS082205, NS098006]
- JPB Foundation
- Parkinson's Disease Foundation [PDF-SFW-1572, PDF-APDA-SFW-1650]
- American Parkinson Disease Association [PDF-SFW-1572, PDF-APDA-SFW-1650]
- Intramural Research Program of the NCI, Center for Cancer Research, NIH
- Foundation's Parkinson's Disease Program [M-1, M-2, H-2013, H-2014]
- NATIONAL CANCER INSTITUTE [ZIABC010390] Funding Source: NIH RePORTER
alpha-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson's disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson's disease, there is evidence that parkin is inactivated in sporadic Parkinson's disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson's disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three alpha-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in alpha-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and alpha-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson's disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson's disease and related alpha-synucleinopathies.
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