Molecular genetics of spinocerebellar ataxia type 8 (SCA8).
Spinocerebellar ataxias (SCAs) belong to a group of autosomal dominant, late-onset neurodegenerative disorders characterized by slowly progressive ataxia that eventually leads to severe gait, speech, coordination and sensory loss. The majority of these diseases result from expanded polyglutamine tracts in the encoded protein as seen in SCA1, SCA2, SCA3, SCA6, SCA7 and Dentatorubral-Pallidoluysian Atrophy (DRPLA). However, two novel forms of SCAs, SCA8 and SCA12, are associated with trinucleotide repeat expansions in non-translated regions of the genes. In the case of SCA8, the CUG expansion occurs at the 3' end of a processed non-coding RNA. While understanding of how expanded polyglutamine tracts compromise or alter protein function has advanced rapidly in the last five years, understanding of how trinucleotide repeat expansions alter the function of the non-coding SCA8 RNA and lead to human disease remains quite limited. Encouragingly, as discussed in this review, recent studies from murine and Drosophila models have provided new insights into both the cellular context in which SCA8 normally operates and the potential role of CTG expansion in the disease. Continued exploration of these genetically tractable model systems will further illuminate the biology underlying SCA8 disease, ultimately providing the necessary foundation on which to develop effective therapeutic interventions.
Mutsuddi
Mousumi
M
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02139, USA.
Rebay
Ilaria
I
D000818:Animals; D006801:Humans; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics*; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D020754:Spinocerebellar Ataxias / Q000235:genetics*
C415906:ATXN8OS gene product, human; D009419:Nerve Tissue Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated