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In vivo study of BIN1, a novel and major gene predisposing to late-onset Alzheimer

Research unit

UMR 7104 - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
1 rue Laurent Fries 67404 ILLKIRCH

Group

Name: Physiopathologie des maladies neuromusculaires

Group leader: LAPORTE Jocelyn - jocelyn@igbmc.fr

Group leader's phone: 0388653412

Website: Visit website

Group organization:
- Chercheurs: 3
- ITA: 2
- Doctorants: 2
- Post-Docs: 3
- Autres: 1

Publications of the team linked to the topic (3 last years):
1) Prokic I, Cowling BS, Laporte J. Amphiphysin 2 (BIN1) in physiology and diseases. J Mol Med (Berl). 2014 Mar 5. [Epub ahead of print]
2) Böhm J, Vasli N, Maurer M, Cowling B, Shelton GD, Kress W, Toussaint A, Prokic I, Schara U, Anderson TJ, Weis J, Tiret L, Laporte J. Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly progressive Centronuclear Myopathy. PLoS Genet. 2013 Jun;9(6):e1003430.
3) Pereira PL, Magnol L, Sahún I, Brault V, Duchon A, Prandini P, Gruart A, Bizot JC, Chadefaux-Vekemans B, Deutsch S, Trovero F, Delgado-García JM, Antonarakis SE, Dierssen M, Herault Y. A new mouse model for the trisomy of the Abcg1-U2af1 region reveals the complexity of the combinatorial genetic code of Down syndrome. Hum Mol Genet. 2009 Dec 15;18(24):4756-69.

About PhD

PhD Director: LAPORTE Jocelyn - jocelyn@igbmc.fr

Phone: 0388653412

Junior advisor: non

Co-tutely: non

Co-Director: HERAULT Yann
University of Co-Director: Strasbourg

About PhD topic :

Title: In vivo study of BIN1, a novel and major gene predisposing to late-onset Alzheimer

Project: Alzheimer's disease (AD) and its related syndromes are the principal causes of dementia. The prevalence of AD in the over-65s is 6% in men and 9% in women, and reaches 40% in the over-85s. In France, there are about 900,000 cases. It is expected that in the next 20 years, the prevalence of AD and related diseases will double in industrialized countries and will quadruple in developing countries. There is no potent treatment and the pathological bases are not well understood.

Very recently, the BIN1 gene encoding for the membrane trafficking regulator amphiphysin 2 has been found to be the second most important susceptibility locus for late-onset Alzheimer's disease after apolipoprotein E (APOE) (http://www.alzgene.org/). BIN1 appears overexpressed in AD brains and represents a novel regulator of the microtubule-associated protein TAU (MAPT) that is found abnormally accumulated in AD. Whether BIN1 may be a biomarker or a therapeutic target for Alzheimer's disease remains to be investigated. Mammalian models are required to understand the implication of BIN1 in AD and investigate the normal role of BIN1 in brain.

The aims of the project are to validate and characterize the first BIN1-related mammalian model for AD, and to achieve proof-of- concept phenotypic rescue.
We have generated several transgenic mouse lines overexpressing BIN1 from a human artificial chromosome (TgBIN1 mice). Preliminary data showed these mice display precursor signs of AD in human, suggesting they represent faithful models. The PhD student will characterize the behavior (memory, cognition), histological and molecular phenotypes of these TgBIN1 mice at different time-points during the progression of the disease. Neuronal loss will be scrutinized. The implication of BIN1 in the formation of amyloid plaques and Tau neurofibrillary tangles will be investigated in these animal models and in derived cellular systems.
Then, rescue experiments will be done by reducing BIN1 levels in the TgBIN1 mice, first through genetic crosses with a BIN1 knock-out mouse already available in the lab, then with Adeno-associated viral vectors (AAV) encoding for shRNA against BIN1. Stereotaxic injection of either BIN1 isoforms or AAV-shRNA against BIN1 into specific brain area will identified which specific areas are implicated in an AD-like phenotype.
Finally, if the above rescue experiments are successful, we will use a similar strategy to rescue other models of AD in mice.

This project should greatly impact on our understanding of Alzheimer's disease, lead to the characterization of the novel BIN1 pathway, and validate therapeutic proof-of-concept in mammals.

Wished skills: -knowledge in cellular biology and physiology
-previous training period in a research lab
-interest for human disease and pathophysiology
-ability to acquire independence
-highly motivated to learn and to work in a team

Expertises which will be acquired during the training: Technical:
-cell biology: cell culture, confocal and in vivo imaging
-behavior analysis of mouse models and histology
-viral-based gene transfer
General:
-management of a research project (choice of strategies, experiments, analysis and validation)
-oral (meetings, congress) and written (articles, posters) communications
-participation to the preparation of grants applications and publications