The RNA binding KH domain of Spoonbill depletes pathogenic non-coding spinocerebellar ataxia 8 transcripts and suppresses neurodegeneration in Drosophila.

Spinocerebellar ataxia 8 (SCA8) pathogenesis is a resultant of gain-of-function machinery that primarily results at the RNA level. It has been reported that expanded non-coding CTG trinucleotide repeat in the ATXN8OS transcripts leads to SCA8 coupled neurodegeneration. Targeted depletion of pathogenic SCA8 transcripts is a viable therapeutic approach. In this report we have focused on the suppression of toxic RNA gain-of-function associated with SCA8. We report suppression of SCA8 associated neurodegeneration by KH RNA binding domain of Spoonbill. KH domain suppresses pathogenic SCA8 associated phenotype in adult flies. Ectopic expression of KH domain leads to massive reduction in the number and size of SCA8 RNA foci. We show that Spoonbill interacts with toxic SCA8 transcripts via its KH domain and promotes its depletion. Till date, no attempts have been made for therapeutic intervention of SCA8 pathogenesis. Further characterization of Spoonbill KH domain may aid us in designing peptide based therapeutics for SCA8 associated neurodegeneration.

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