期刊
MOLECULAR NEURODEGENERATION
卷 11, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/s13024-016-0079-2
关键词
p53; alpha-synuclein; Transcription
资金
- Conseil General des Alpes Maritimes
- Foundation Claude Pompidou
- LABEX (excellence laboratory, program investment for the future) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
Background: Parkinson's disease (PD) is a motor disease associated with the degeneration of dopaminergic neurons of the substantia nigra pars compacta. p53 is a major neuronal pro-apoptotic factor that is at the center of gravity of multiple physiological and pathological cascades, some of which implying several key PD-linked proteins. Since p53 is up-regulated in PD-affected brain, we have examined its ability to regulate the transcription of alpha-synuclein, a key protein that accumulates in PD-related Lewy bodies. Results: We show that pharmacological and genetic up-regulation of p53 expression lead to a strong increase of alpha-synuclein protein, promoter activity and mRNA levels. Several lines of evidence indicate that this transcriptional control is due to the DNA-binding properties of p53. Firstly, p53 DNA-binding dead mutations abolish p53 regulation of alpha-synuclein. Secondly, the deletion of p53 responsive element from alpha-synuclein promoter abrogates p53-mediated alpha-synuclein regulation. Thirdly, gel shift and chromatin immunoprecipitation studies indicate that p53 interacts physically with alpha-synuclein promoter both in vitro and in a physiological context. Furthermore, we show that the depletion of endogenous p53 in cells as well as in knockout mice down-regulates alpha-synuclein transcription. Conclusions: Overall, we have identified alpha-synuclein as a new transcriptional target of p53 and delineated a cellular mechanism feeding the accumulation of toxic aggregated alpha-synuclein in PD. This original alpha-syn regulatory mechanism may be central to PD-related cell death and may lead to novel opportunities to design alternative neuroprotective strategies in PD.
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