Contribution des neurones inhibiteurs au continuum formé par la sclérose latérale amyotrophique et la démence frontotemporale : étude des phénotypes moteurs et sociaux associés à la protéine FUS

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive, invalidating and fatal neurodegenerative disorders forming a continuum. ALS is primarily characterised by the degeneration of motor neurons resulting in paralysis. FTD is defined by a degeneration of the frontal and temporal lobes, which causes behavioural and cognitive decline. The cytoplasmic accumulation of fused in sarcoma (FUS), a ubiquitous and multifunctional DNA/RNA-binding protein, is involved in the aetiology of ALS and FTD. Inhibitory neurons impairments appear to be an early feature of both diseases, and may contribute to the onset and progression of symptoms. However, the role of inhibitory neurons in FUS-related phenotypes remains to be elucidated. Here, we generated novel mouse models in which the subcellular localisation of FUS can be manipulated in cells expressing the vesicular GABA transporter (VGAT). Our findings demonstrate that the localisation of FUS in cerebral and spinal GABAergic and glycinergic neurons is a key regulator of motor and social phenotypes, as well as neuronal activity.