PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis - PubMed
12 hours ago
- #C9orf72
- #ALS
- #DNA damage
- A hexanucleotide (GGGGCC) repeat expansion in the C9orf72 gene is the most frequent genetic cause of ALS and FTD, leading to reduced C9orf72 mRNA and protein expression.
- C9orf72-associated cerebellar pathology is implicated in neurodegenerative disorders, including ALS/FTD, but the pathogenic mechanisms are not fully understood.
- Loss of C9orf72 function in vivo results in cerebellar atrophy, loss of GABAergic interneurons, and depletion of Purkinje and Granule cells, which precede motor defects.
- Single-cell transcriptomics in C9orf72-zebrafish brains showed downregulation of the purine biosynthetic gene paics in Purkinje cells.
- Reduced PAICS expression was found in human post-mortem cerebellar sections and iPSC-derived motor neurons from C9orf72 and sporadic ALS patients.
- Knockout of paics in zebrafish mimics cerebellar neuronal loss, neuromuscular junction disruption, motor impairment, and widespread DNA damage and repair defects.
- Restoring paics expression in C9orf72 zebrafish resolves DNA damage and preserves Purkinje and Granule cells, highlighting PAICS as a key mediator of cerebellar degeneration and a potential therapeutic target for C9orf72-associated ALS and FTD.