Molecular Pathogenesis of Spinocerebellar Ataxia type 10

Microsatellite plays a major pathogenic role in repeat expansion disorder. This heterogeneous group of disease is caused by the expanded sequences of nucleotide repeat within a target gene. Spinocerebellar ataxia type 10 (SCA10) is a unique autosomal dominant cerebellar ataxia (ADCA). The presence of seizure in addition to pancerebellar ataxia is a characteristic clinical manifestation of SCA10. More interestingly, the genetic mutation to cause SCA10 is a non-coding ATTCT repeat expansion located on the 9th intron of the ATXN10 gene. 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 is focusing on elucidating a molecular pathogenesis of this unique inherited disease.

In this study, we demonstrate normally transcribed ATTCT-repeat forms a lengthy AUUCU pre-mRNA molecule in SCA10 cells, after being completely spliced out. We identify 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 indicates that the sequestration of the RNA-binding proteins by toxic expanded repeat results in complex SCA10 phenotype. We clearly show that aberrant splicing of GABAARγ2 and GlyRα2 causes disruption of inhibitory transmission in Purkinje cells in SCA10 cerebellum. We demonstrate that abnormal electrophysiology in SCA10 occurs specifically through modulating GABA neurotransmission but not glycine.

In our current study, we are able to define SCA10 as a toxic RNA disease, and present one of the possible molecular and electrophysiological mechanisms of SCA10 pathophysiology.