CAG Repeat Instability and Region-Specific Gene Expression Changes in the SCA12 Brain

Spinocerebellar ataxia type 12 (SCA12), an autosomal dominant cerebellar ataxia, caused by an expansion of (CAG)_n in the 5' of the PPP2R2B gene on chr5q32, is common in India. The illness often manifests late in life, with diverse neurological and psychiatric symptoms, suggesting involvement of different brain regions. Prominent neuronal loss and atrophy of the cerebellum have been noted earlier. In Huntington's disease (HD), somatic instability associated with the size of the expanded CAG allele in HTT varies across regions of the brain, and influences the nature and severity of symptoms. We estimated CAG repeat size, methylation and gene expression in the PPP2R2B gene across regions in brain tissue from a person with SCA12. We also studied the regional expression of DNA repair pathway and cell cycle genes. Somatic mosaicism, manifested as CAG repeat instability, is detected across brain regions. The cerebellum showed the least somatic instability, and this was coupled with increased methylation, and lower expression, of the PPP2R2B gene. Interestingly, increased expression of DNA maintenance pathway related genes, which might partly explain the lowered DNA instability, was also observed. There was also decreased expression of cell cycle modulators, which could initiate apoptosis, and thus account for neuronal cell death seen in the brain sections. We suggest that drugs that improve DNA repeat stability, could thus be explored as a treatment option for SCA12.