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Reference : UMR7275-CRIALV-004
Workplace : VALBONNE
Date of publication : Thursday, July 15, 2021
Scientific Responsible name : Cristine Alves da Costa
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 October 2021
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
Parkinson's disease (PD) is a neurodegenerative syndrome characterized by a selective loss of dopaminergic neurons probably due to exacerbated cell death. PD can be of sporadic and genetic origin but even if the latter is less common, these two forms are characterized by common pathological dysfunctions. Thus, the study of genetic forms greatly contributes to deciphering the molecular mechanisms responsible for sporadic forms. Our laboratory is interested in parkin, a protein responsible for autosomal recessive forms of PD. Parkin is widely known for its ubiquitin-ligase function. However, we have shown that it is also a transcription factor capable of regulating genes involved in PD, but also other neurodegenerative pathologies. We have shown that parkin regulates the transcription of two key genes linked to Alzheimer's disease (AD) which are presenilins 1 and 2 (PS1, PS2). Given the major role of PSs in gamma-secretase activity and cognitive deficit in AD, our main objective will be to establish the involvement of parkin as a transcription factor in the process of loss of memorization associated with AD. This project should make it possible to establish the molecular steps ex-vivo, in various relevant cell models and to examine their relevance, in vivo, in animal models of AD and MP (transgenic parkin).
Techniques: The project involves cell models and animal models. The following will be used: RNAseq, ChIPseq, electrophysiology, cell culture, real-time PCR, immunoblotting, enzymatic assays, immunohistochemical labeling and molecular biology (cloning, site-directed mutagen). Our in vivo experiments will require the subcloning of DNAs into lentiviral vectors. These constructions will be injected into "control" mice and transgenic for the various proteins associated with the family forms of the pathology.
1. da Costa, C. et al. Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease. Nature Cell Biology 11, 1370-1375 (2009).
2. Duplan, E. et al. Parkin differently regulates presenilin-1 and presenilin-2 functions by direct control of their promoter transcription. Journal of molecular cell biology 5, 132-142 (2013).
3. Goiran, T. et al. beta-Amyloid Precursor Protein Intracellular Domain Controls Mitochondrial Function by Modulating Phosphatase and Tensin Homolog-Induced Kinase 1 Transcription in Cells and in Alzheimer Mice Models. Biol Psychiatry 83, 416-427 (2018).
This thesis will be carried out at the Institute of Molecular and Cellular Pharmacology (IPMC, UMR 7275, CNRS / Université Côte d'Azur), in the "Cellular and Molecular Biology of normal and pathological brain aging" team. The laboratory is located in Valbonne, in the south-east of France, on the Sophia-Antipolis technology park.
Constraints and risks
The project involves surgery in mice so permission to perform animal experiments is a plus.
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