Molecular Pathogenesis of Spinocerebellar Ataxia type 10
Lim, Jung gook 1971-
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Spinocerebellar ataxia type 10 (SCA10) is a unique autosomal dominant cerebellar ataxia (ADCA) which habors non-coding ATTCT repeat expansion on the 9th intron of the ATXN10 gene. The presence of seizure in addition to pancerebellar ataxia is a characteristic clinical manifestation of SCA10. How this enlarged intronic ATTCT repeat leads to degeneration or dysfunction of the nervous system underlying SCA10 phenotype is not well known. The present study focused on elucidating a molecular pathogenesis of this unique inherited disease. In this study, we demonstrated normally transcribed ATTCT-repeats form a lengthy AUUCU pre-mRNA molecule in SCA10 cells, after being completely spliced out. We identified the specific interaction between this AUUCU RNA repeat and a RNA-binding protein, Nova, which leads to the aberrant splicing of Nova target transcripts, including major inhibitory neurotransmitter receptors, glycine and GABA. Our study also indicated that the sequestration of the RNA-binding proteins by toxic expanded repeats result in complex SCA10 phenotype. We clearly showed that aberrant splicing of GABAARγ2 and GlyRα2 causes disruption of inhibitory transmission in Purkinje cells in the SCA10 cerebellum. We demonstrated that abnormal electrophysiology in SCA10 occurs specifically through modulating GABA neurotransmission but not glycine. In our current study, we were able to define SCA10 as a toxic RNA disease, and presented one of the possible molecular and electrophysiological mechanisms of SCA10 pathophysiology.