Purine Biosynthetic Enzyme PAICS as a Central Mediator of DNA Damage and Cerebellar Atrophy in C9orf72-ALS

Highlights

• C9orf72 loss-of-function in vivo triggers cerebellar atrophy and depletion of Purkinje and Granule cells, preceding the onset of overt motor defects.
• Single-cell transcriptomics identifies the downregulation of paics, a gene essential for purine biosynthesis, as a primary driver of neuronal loss in the cerebellum.
• PAICS deficiency is validated in human post-mortem cerebellar tissue and C9orf72 iPSC-derived motor neurons, suggesting a conserved mechanism across species.
• Knockout of paics leads to catastrophic DNA damage and repair (DDR) defects; conversely, restoring PAICS expression rescues the neurodegenerative phenotype and motor function.

Background