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phD student: Role of C99 oligomerization and its exosomal spread in Alzheimer's disease

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Français - Anglais

Date Limite Candidature : mardi 25 mai 2021

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General information

Reference : UMR7275-INGLAU-001
Workplace : VALBONNE
Date of publication : Tuesday, May 04, 2021
Scientific Responsible name : Inger Lauritzen
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 27 September 2021
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly

Description of the thesis topic

-Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and cause of dementia in elderly. AD brains are known to be filled with extracellular Aβ deposits and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. Up to recently, Aβ was thought the trigger of AD, but the consistent failure of therapies aiming at decreasing Aβ production or neutralizing it once formed, have questioned this dogma and have suggested a pathogenic role of alternative candidates. Emerging evidence proposes that the β-secretase derived APP fragment C99 (βCTF), corresponding to the direct precursor of Aβ, is one of these candidates. For instance, we demonstrated that C99, rather than Aβ, cause endolysosomal network (ELN) dysfunction representing one of the earliest features of AD pathology (1,2). This dysfunction is known also to involve exosomes, small nano-sized vesicles formed within endosomes, secreted from the cells and implicated in Prion-like inter cellular transmission of pathogenic proteins. In AD models, exosomes are enriched in C99 and our recent studies showed that these vesicles also contain C99 existing as oligomers (3), although the pathological contribution of these oligomers remains unknown. The phD project aims at investigating C99 oligomerization and exosomal spread of C99, which should allow to better understand the role of C99 in AD onset and progression.
Methods: This project is mainly based on cellular biology and imaging techniques. C99 oligomerization will be visualized using two distinct real-time imaging techniques (bimolecular fluorescence complementation, BIFC) (4,5) and light-inducible protein aggregation (LIPA)) (6). Both systems should allow monitoring C99 oligomerization in living cells and by real-time confocal imaging. After validation of these techniques in cultured cell lines, similar approaches will be carried out in mouse hippocampal slice cultures and then in mice using viral vectors to induce protein expression.
related publications:
1. Lauritzen, I., Pardossi-Piquard, R., Bauer, C., Brigham, E., Abraham, J. D., Ranaldi, S., Fraser, P., St-George-Hyslop, P., Le Thuc, O., Espin, V., Chami, L., Dunys, J., and Checler, F. (2012) J Neurosci 32, 16243-16255a
2. Lauritzen, I., Pardossi-Piquard, R., Bourgeois, A., Pagnotta, S., Biferi, M. G., Barkats, M., Lacor, P., Klein, W., Bauer, C., and Checler, F. (2016) Acta Neuropathol 132, 257-276
3. Lauritzen, I., Becot, A., Bourgeois, A., Pardossi-Piquard, R., Biferi, M. G., Barkats, M., and Checler, F. (2019) Transl Neurodegener 8, 35
4. Kerppola, T. K. (2008) Methods Cell Biol 85, 431-470
5. Meckler, X., and Checler, F. (2014) J Alzheimers Dis 40, 161-176
6. Taslimi, A., Vrana, J. D., Chen, D., Borinskaya, S., Mayer, B. J., Kennedy, M. J., and Tucker, C. L. (2014) Nat Commun 5, 4925

Work Context

-The candidate will join the Frédéric Checler's team within the Institute of Molecular and Cellular Pharmacology (IPMC), which is also integrated in the Laboratory of Excellence Distalz, Transdisciplanary Approaches for Innovative Strategies in Alzheimer's disease composed of 7 different laboratories in France working on Alzheimer's disease. IPMC was founded in 1989 in the Tecnhnology park Sophia Antipolis (French Riviera), and is a joint laboratory between the Centre National de la Recherche Scientifique (CNRS) and the University Côte d'Azur. The 19 international research teams take advantage of state-of-the-art equipment and high level of expertise in molecular & cellular biology, imaging, cytometry, electrophysiology, functional genomics, mass spectrometry and animal facility.
The institute, ranked A+ (the highest grade awarded by the by the French National Agency for Research and Higher Education). WEB site: https://www.ipmc.cnrs.fr/cgi-bin/site.cgi. The candidate will join the doctoral school at the University of Côte d'Azur (UCA) and may benefit from doctoral courses proposed by the university.

Constraints and risks

No contraints
Biological and chemical risks

Additional Information

3-year Doctoral fellow from the “Vaincre Alzheimer foundation”

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