Partial inhibition of the overactivated Ku80-dependent DNA repair pathway rescues neurodegeneration in C9ORF72 -ALS/FTD

Significance GGGGCC (G4 C2 ) repeat expansion in theC9ORF72 gene is the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Several dysregulated downstream molecular pathways have been identified; however, it is not known which pathway is primarily responsible for neurodegeneration, and effective therapeutic approaches remain elusive. In cellular and animal models ofC9ORF72 -ALS/FTD, we found that partial inhibition of an overactivated DNA repair pathway, and of Ku80 in particular, suppresses a cell death pathway, suggesting a therapeutic approach inC9ORF72- ALS/FTD.