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
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