Molecular mechanisms and therapeutic strategies in amyotrophic lateral sclerosis caused by mutations in the C9orf72 gene. (360G-Wellcome-107196_Z_15_Z)

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by motor neuron degeneration. A hexanucleotide expansion in the C9orf72 gene is a common cause of ALS and my supervisors (Isaacs and Partridge) recently published evidence from a Drosophila model in the journal Science that neurotoxicity is mediated by dipeptide repeat (DPR) proteins generated by repeat-associated non-ATG translation. Emerging evidence suggests that DPR proteins cause nucleolar dy sfunction and resolving this in relevant disease models will significantly increase our understanding of and ability to treat C9orf72-ALS. Aims: Using C9orf72-ALS models I will evaluate if DPR proteins cause nucleolar dysfunction and interact with RNA and whether promising novel small molecules which bind C9orf72 repeat RNA reduce DPR formation, nucleolar dysfunction and neurotoxicity. Methods: I propose a carefully integrated approach that will combine assessment of nucleolar function an d therapeutic potential of the small molecules in 1) novel in vivo Drosophila models, with subsequent validation in 2) C9orf72 mutation human induced pluripotent stem cell (iPSC)-derived spinal motor neurons. This approach across model systems will serve to rigorously validate the findings made. Implications: These experiments may provide novel mechanistic insights into a common form of ALS and deliver pre-clinical data on an exciting therapeutic approach.