Volume 8 Supplement 1

Molecular Neurodegeneration: Basic biology and disease pathways

Open Access

Parkin acts as a transcription factor modulating presenilin-1 and presenilin-2 promoter transactivations

  • Eric Duplan1,
  • Jean Sévalle1,
  • Julien Viotti1,
  • Thomas Goiran1,
  • Charlotte Bauer1,
  • Paul Renbaum2,
  • Ephrat Levy-Lahad2,
  • Clément A Gautier3,
  • Olga Corti3,
  • Nathalie Leroudier1,
  • Frédéric Checler1 and
  • Cristine Alves da Costa1
Molecular Neurodegeneration20138(Suppl 1):P56

https://doi.org/10.1186/1750-1326-8-S1-P56

Published: 4 October 2013

Background

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 [1]. 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.

Results

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 [2].

Conclusions

This study is a "framework" for the identification of novel transcriptional targets of parkin and for a better comprehension of parkin's functions.

Declarations

Acknowledgements

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.

Authors’ Affiliations

(1)
IPMC-CNRS UMR 7275
(2)
Medical Genetics Institute, Shaare Zedec Medical Center, Hebrew University Medical School
(3)
INSERM U679, Hôpital de la Pitié-Salpêtrière

References

  1. da Costa CA, et al: Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease. Nat Cell Biol. 2009, 11 (11): 1370-1375. 10.1038/ncb1981.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Duplan E, et al: Parkin differently regulates presenilin-1 and presenilin-2 functions by direct control of their promoter transcription. J Mol Cell Biol. 2013, 5 (2): 132-142. 10.1093/jmcb/mjt003.View ArticlePubMedGoogle Scholar

Copyright

© Duplan et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.