RNA gain of function effects in spinocerebellar ataxia type 8

Spinocerebellar ataxia type 8 (SCA8) is a dominantly inherited, slowly progressive neurodegenerative disorder caused by a CTG•CAG repeat expansion located on chromosome 13q21. Affected individuals show relatively pure cerebellar symptoms affecting gait and limb coordination, speech and eye movements. The SCA8 CTG•CAG expansion, which shows dramatic genetic instability, was the first apparently non-coding triplet repeat reported to cause ataxia. Our lab recently reported a transgenic mouse model in which SCA8 expansion but not control mice develop a progressive neurological phenotype. In addition in vivo optical imaging studies have shown that reduced cerebellar GABA-ergic inhibition. Additional studies demonstrate that the SCA8 (CTG•CAG)n expansion is expressed in both directions (CUG and CAG) and that a novel gene expressed in the CAG direction encodes a pure polyglutamine (polyQ) expansion protein (ataxin-8). These data suggest that SCA8 pathogenesis could be caused by either or both of the following mechanisms: (1) protein gain of function effects caused by toxicity of the polyglutamine protein expressed in the CAG direction or (2) RNA gain of function effects caused by the accumulation of CUG expansion transcripts. My hypothesis is that expression of CUG expansion transcripts in SCA8 causes RNA gain of function effects by cell type specific nuclear accumulation in the brain and the depletion or dysregulation of specific RNA binding proteins (MBNL1 and CUGBP1) involved in alternative splicing of genes normally regulated during development. This thesis supports this hypothesis and shows that (1) CUG/Mbnl1 foci accumulate in SCA8 brains; (2) rotarod deficits in SCA8 mice are enhanced by reduced Mbnl1; and (3) SCA8 CUG expansion transcripts dysregulate the GABA-A transporter-4 (Gabt4) gene through the dysregulation of CUG-BP1 and Mbnl1 pathways. These data show that Gabt4, a CNS specific gene, is upregulated by SCA8 CUG expansion transcripts in SCA8 brain and demonstrate that dysregulation of Mbnl1 and CUG-BP1, which play a prominent role in RNA gain of function effects in skeletal muscle, also cause disease specific CNS changes.