PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis
Jaskaran Singh·Shunmoogum A Patten·Mathilde Chaineau·Léa Lescouzères·Thomas M Durcan·Ghazal Haghi·Charlotte Zaouter
A hexanucleotide (GGGGCC) repeat expansion in C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), resulting in reduced C9orf72 mRNA and protein expression. C9orf72 is highly expressed in the cerebellum and growing evidence implicates C9orf72-associated cerebellar pathology across neurodegenerative disorders including ALS/FTD, yet the pathogenic mechanisms remain unresolved. Here, we demonstrate in vivo C9orf72 loss of