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Role Of C9orf72 In Amyotrophic Lateral Sclerosis

Reference : PhD Nicolas Charlet-Berguerand

Offer publication : Jan. 26, 2018

Amyotrophic Lateral Sclerosis (ALS) is the third most common neurodegenerative disease in the western world, affecting 1 individual in 50,000 people. This devastating disease is characterized by degeneration of motor neurons leading to muscle wasting and weakness, ultimately resulting in paralysis and death of patients. ALS is increasingly recognized as a multisystem disorder with impairment of frontotemporal functions such as cognition and behavior in up to 30% of patients resulting in Frontotemporal Dementia (FTD).


Recently, the most common genetic cause of ALS-FTD was identified as an expansion of CGGGGC repeats located within the first intron of the C9ORF72 gene. This mutation leads to expression of toxic dipeptide proteins translated from the GGGGCC repeats, and to decreased expression of the C9ORF72 gene. Currently, it is unclear which one of these mechanisms is the leading cause of motor neuron degeneration and death.


Our recent results (Sellier et al., 2016) indicate that C9ORF72 regulates macroautophagy, a catabolic process necessary to neurons. Furthermore, we identified various mutations of C9ORF72 in ALS patients. Our hypothesis is that these mutations may alter autophagy and consequently contribute to the neurodegenerescence observed in ALS-FTD. We are developing novel cell and mouse models that express these C9ORF72 mutations.


Thus, topic of this PhD project will be to characterize these novel models, notably alterations of autophagy and neuronal cell death. The candidate will investigate at the molecular and cellular level the effect of C9orf72 mutations on the autophagic clearence of protein aggregates (polyQ protein) and altered mitochondria (CCP treatment) using transformed and primary neuronal cell cultures and classic molecular and cellular approaches (RT-PCR, western, immunofluorescence,  transfection and cell transduction, etc.). Furthermore, the candidate will study the phenotypes of mice expressing C9ORF72 mutations. This study will comprise animal behavior and motor performances using classic tests such as rotarod, grip test, catwalk, Y-maze, etc ; followed by molecular (RNA seq, qRT-PCR and western blotting)) and histological analyses (immunofluorescence, IHC).


Overall, this proposal will help to better understand the cause of neuronal degeneration in ALS-FTD patients, in order to define therapeutic strategy and drug screening design.

Your application

Application Deadline : Nov. 1, 2018

Imprimer Envoyer

Université de Strasbourg

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