ERK活化於SCA17小鼠病理機制之意義

Spinocerebellar ataxia type17 (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. Mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways have been implicated in neuronal apoptosis. Our previous study identified the elevated ERK activation in the SCA17 cerebella, and we now aim to study the role of ERK activation in SCA17. We have generated SCA17 transgenic mice bearing human TBP with 109 CAG repeats. These mice recapitulate the patients' phenotypes and are suitable for the study of the SCA17 pathomechanism. Western blot and co-immunostaining were performed to identify the expression of ERK, calbindin, and gliosis markers on the mouse cerebellum at 2-8 weeks old to elucidate the correlation between elevated ERK activation and Purkinje cell degeneration. Behavior analyses showed that the motor incoordination was initiated in SCA17 mice at 6 weeks old. We found that the degeneration of Purkinje cells occurred in the SCA17 mice at 4 weeks old. The presence of TBP nuclear aggregation and microglia activation were also observed at that point. Moreover, gliosis of astrocytes and Bergmann glia, pERK, Bax/Bcl2 ratio, and caspase-3 were significantly increased in the 6-week-old SCA17 mouse cerebellum. Our study suggests that the activation of pERK contribute to the elevated gliosis and the neuronal apoptosis in the SCA17 mice.