PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis.

ABSTRACT: 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 function leads to cerebellar atrophy, loss of GABAergic interneurons, and depletion of Purkinje and Granule cells. Additionally, we demonstrate that these cerebellar anomalies precede motor defects. Single-cell transcriptomics of the C9orf72-zebrafish brain revealed the downregulation of a purine bi

SUBMITTER: Singh J 

PROVIDER: S-EPMC13634648 | biostudies-literature | 2026 Mar

REPOSITORIES: biostudies-literature