Molecular Basis Of Amyotrophic Lateral Sclerosis
Reference : PhD Nicolas CHARLET-BERGUERAND
Offer publication : April 5, 2016
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 behaviour in up to 30% of patients. Frontotemporal Dementia (FTD) is the second most common cause of presenile dementia in which degeneration of the frontal and temporal lobes of the brain results in progressive changes in personality, behaviour, and language. The concept that FTD and ALS represent two extreme of a common spectrum of disease is now demonstrated by clinical, histopathological and genetic evidences.
Recently, the most common genetic cause of ALS-FTD was identified as a non-coding expansion of CGGGGC repeats located within the first intron of the C9ORF72 gene. This mutation leads to expression of an RNA containing expanded CCGGGG repeats, expression of dipeptide 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. Also, while mutation in the C9ORF72 gene is the most common cause of ALS-FTD, there is little, yet, known on
the function of the C9ORF72 gene.
Our preliminary results indicate that C9ORF72 form a complex with SMCR8, a protein of unknown function. We found that the C9ORF72/SMCR8 complex regulates autophagy, and that mis-regulation of autophagy may indeed contribute to the neurodegenerescence observed in ALS-FTD. We developped novel mouse models that are knockout for SMCR8 or C9ORF72 gene. Topic of this PhD project will be to study the phenotypes of mice invalidated for SMCR8 and/ or C9ORF72 expression. The PhD student will investigate the behavior and motor performances using classic tests such as rotarod, grip test, catwalk, Y-maze, etc ; followed by EMG, molecular (RNA seq, qRT-PCR and western blotting)) and histological analyses
(immunofluorescence, IHC). Furthermore, the PhD student will investigate the molecular and cellular characteristic of depleting C9orf72 and/or SMCR8 in primary neuronal cell cultures of mouse embryo using lentiviral transduction and classic molecular and cellular tools (RT-PCR, western, immunofluorescence, transfection and cell transduction, etc.). 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.
- WISHED SKILLS : Basic knowledge in molecular and cellular biology
- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : Molecular Biology (clonage, RT-qPCR, etc.), Cellular (transfection, lentiviral production and transduction, primary cultures of neuronal murine cells, etc.), Physiology (study of behavior and motor activity in mouse models, etc.).
Application Deadline : Dec. 31, 2016