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

Significance GGGGCC (G 4 C 2 ) repeat expansion in the C9ORF72 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 of C9ORF72 -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 in C9ORF72- ALS/FTD.