Dissecting molecular mechanism of spinocerebellar ataxia type 31

Abstract

Spinocerebellar ataxia is a group of neurodegenerative disorders clinically presenting adult onset cerebellar ataxia. To date, 21 different genes (SCA1, 2, 3, 5, 6, 7, 8, 10, 11,12,13,14,15,17, 23, 27, 28, 31, 35, 36 and DRPLA) and additionally 10 different gene loci (SCA4,18,19, 20, 21, 25, 26, 29, 30 and 32) are identified. Among these, SCA6 and SCA31 are the two common diseases clinically presenting as a relatively predominant cerebellar syndrome, whereas Machado-Joseph disease/SCA3, DRPLA, SCA1 and SCA2 are SCAs often associated with extracerebellar manifestations. SCA31 is a late-onset purely cerebellar ataxia caused by a complex pentanucleotide repeat containing (TGGAA) n lying in an intronic region shared by two genes, BEAN (brain expressed, associated with NEDD4) and TK2 (thymidine kinase 2). In situ hybridization analysis in patients' Purkinje cells demonstrated that pentanucleotide repeats transcribed in BEAN direction form RNA aggregates ("RNA foci"), and essential splicing factors, SFRS1 and SFRS9, bind to (UGGAA) n, the transcript of (TGGAA) n in vitro. Our preliminary data also demonstrated that (UGGAA) n is toxic when expressed in cultured cells. These findings may imply that RNA-mediated pathogenesis is involved in SCA31. Further studies are needed to explore precise mechanism of this disease.