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Abstract
BackgroundParkinson’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 α-synuclein, a key protein that accumulates in PD-related Lewy bodies.ResultsWe show that pharmacological and genetic up-regulation of p53 expression lead to a strong increase of α-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 α-synuclein. Secondly, the deletion of p53 responsive element from α-synuclein promoter abrogates p53-mediated α-synuclein regulation. Thirdly, gel shift and chromatin immunoprecipitation studies indicate that p53 interacts physically with α-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 α-synuclein transcription.ConclusionsOverall, we have identified α-synuclein as a new transcriptional target of p53 and delineated a cellular mechanism feeding the accumulation of toxic aggregated α-synuclein in PD. This original α-syn regulatory mechanism may be central to PD-related cell death and may lead to novel opportunities to design alternative neuroprotective strategies in PD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0079-2) contains supplementary material, which is available to authorized users.
Highlights
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
This original α-syn regulatory mechanism may be central to PD-related cell death and may lead to novel opportunities to design alternative neuroprotective strategies in PD
Our study demonstrates that both selective pharmacological treatments and genetic manipulation of p53 by overexpression or invalidation approaches trigger a modulation of Duplan et al Molecular Neurodegeneration (2016) 11:13 α-syn transcription by a mechanism implying the physical interaction of p53 with α-syn promoter
Summary
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 α-synuclein, a key protein that accumulates in PD-related Lewy bodies. Parkinson’s disease (PD) is a major age-related motor disease in which several causative genes have been identified Amongst these genes, α-synuclein (α-syn) has caught a special attention given its important role in PD etiology [1, 2]. We previously showed that it exerts an anti-apoptotic phenotype by down-regulating p53 expression and transcriptional activity in neuronal cells [4, 5]. This neuroprotective phenotype can be abrogated by various processes leading to its accumulation and/or aggregation. We have shown that 6-hydroxydopamine, an endogenously produced dopamine catabolite frequently used to trigger PD ex-vivo and in vivo, leads to α-syn aggregation and abolishes α-syn ability to repress p53 [6]
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