ERK activation precedes Purkinje cell loss in mice with Spinocerebellar ataxia type 17

Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant neurodegenerative disease caused by CAG expansion in the gene encoding the TATA-binding protein (TBP). The neurological features of SCA17 are Purkinje cell loss and gliosis. We have generated SCA17 transgenic mice which recapitulate the patients' phenotypes and are suitable for the study of the SCA17 pathomechanism. Our previous study identified the activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) occurred in the SCA17 cerebella, this study aims to study the role of ERK activation in SCA17. The levels of pERK, calbindin, and gliosis markers on the mouse cerebellum at 4-8 weeks old were analyzed to elucidate the correlation among behavioral performance, ERK activation and Purkinje cell degeneration. The motor incoordination was initiated in SCA17 mice at 6 weeks old. We found that the presence of TBP nuclear aggregation and microglia activation were observed at 4 weeks old. Gliosis of astrocytes and Bergmann glia, pERK, Bax/Bcl2 ratio, and caspase-3 were significantly increased in the 6-week-old SCA17 mouse cerebellum. In addition to the polyglutamine-protein aggregation in Purkinje cells caused apoptosis cell-autonomously, a significant body of evidence have shown that ERK pathways involves in neuronal apoptosis. Our study showed that the activation of ERK in the astrocytes and Bergmann glia was identified as preceding motor deficits, which suggest the elevated gliosis by ERK activation may contribute to neuronal apoptosis in SCA17 mice.