Recent topics of spinocerebellar ataxia type 31

Abstract

AbstractSpinocerebellar ataxia type 31 (SCA31) is an autosomal‐dominant neurodegenerative condition caused by a 2.5–3.8 kb‐long complex repeat containing (TGGAA/TTCCA)n in an intron shared by two genes called brain expressed, associated with Nedd4 (BEAN1) and thymidine kinase 2 (TK2) located in the human chromosome 16q22.1. Since BEAN1 and TK2 are transcribed in mutually opposite directions in human brains, two independently transcribed RNAs containing either (UGGAA)n or (UUCCA)n are likely to associate with the pathogenesis of SCA31. Recently, a minor TK2 mRNA isoform called TK2‐EXT was confirmed to be transcribed in human cerebellum, suggesting that (UUCCA)n is indeed expressed. The level of TK2 mRNA and TK2 protein expression levels was both preserved in SCA31 human cerebellum, suggesting that the expression of (UUCCA)n does not affect the expression of TK2, and hence, the function of TK2 seemed to be preserved. On the other hand, the other penta‐nucleotide RNA repeat (UGGAA)n, expressed through BEAN1 transcription, is likely to conform toxicity through forming abnormal RNA structures called RNA foci in the nucleus of expressing cells. In addition, three proteins TDP‐43, FUS, and hnRNPA2/B1 that commonly have a capacity to bind with (UGGAA)n reduced the number of RNA foci, and ameliorated the phenotype brought by (UGGAA)n in Drosophila. A small compound naphthyridine carbamate dimer that binds to (UGGAA)n dampened the (UGGAA)n toxicity in Drosophila, further supporting the idea that (UGGAA)n expressed by BEAN1 is pathogenic. Therefore, a plausible approach to treat SCA31 may be considered by administering agents with a capacity binding to (UGGAA)n.