Parkin acts as a transcription factor modulating presenilin-1 and presenilin-2 promoter transactivations
© Duplan et al; licensee BioMed Central Ltd. 2013
Published: 4 October 2013
Parkin is associated to autosomal recessive early-onset Parkinson's disease. Parkin acts as an E3-ubiquitin ligase involved in the proteasome-mediated degradation of various substrates. It has been suggested that pathogenic mutations of parkin, abolishing its ubiquitin-ligase activity, could explain the accumulation of proteins and lead to neuronal death by apoptosis. However, besides this function, additional parkin-dependent cellular pathways exist. We demonstrated that parkin is a direct transcriptional repressor of the tumor suppressor p53 . p53 regulates the expression and functions of presenilin-1 (PS1) and presenilin-2 (PS2), two members of the gamma secretase complex involved in the production of the amyloid β peptide (Aβ) and parkin could control the homeostasis of intracellular Aβ. These findings prompted us to investigate whether parkin could control presenilins and if so, whether it is via a direct transcriptional control of PS promoters or indirectly, via p53.
Materials and methods
Experiments were conducted on TSM1 neurons, SH-SY5Y human neuroblastoma cells, human embryonic kidney 293 cells, and immortalized mouse embryonic fibroblasts invalidated or not for parkin, presenilin 1 and/or 2, p19 arf and both p19 arf p53. We also used primary cultured neurons and brain extract from mouse invalidated or not for parkin.
We did Q-PCR, Western-blot, caspases-3 activity measurement and in vitro gamma secretase assays experiments. We document by chromosome immune-precipitation, gel shift, gene reporter and mutagenesis experiments parkin direct interaction with presenilins promoters.
Parkin controls presenilin 1 and 2 expressions, promoter activity, and mRNA levels ex vivo and in mouse brains. This regulation impacts on PS-dependent γ-secretase activity and presenilin-mediated control of cell death. This control is independent of parkin ubiquitin-ligase activity, does not involve p53 and is not affected by PS1 and PS2 functional interplay. Parkin binds to presenilins promoters via a consensus binding sequence that we identify and validate by functional analysis .
This study is a "framework" for the identification of novel transcriptional targets of parkin and for a better comprehension of parkin's functions.
This work was supported by the ‘Fondation pour la Recherche Médicale', the ‘Conseil Général des Alpes Maritimes', and the LABEX (excellence laboratory, program investment for the future) DISTALZ.
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