Prof. Hidehiro Mizusawa

Prof. Mizusawa

ISP2012 Symposium Talk Abstract:

Spinocerebellar ataxia type 31: A new RNA disease

Hereditary ataxias consist of autosomal dominant (AD), autosomal recessive (AR) and X-linked recessive forms of ataxia in which the cerebellum, brainstem, spinal cord and other parts of the nervous system are affected by neurodegeneration. AD and AR ataxias comprise more than 30 diseases, frequencies of which are quite different among various ethnicities. In Japan, for example, most cases are AD and there has not yet been a case of Friedreich's ataxia, which is the most common ataxia in Caucasians. Spinocerebellar ataxia type 3 (SCA3), SCA6, SCA31 and DRPLA are the four most common ataxias in Japan. SCAs 6 and 31 are pure cerebellar ataxias, while SCA3 and DRPLA are multiple system-involved ataxias. Approximately 20 years ago, we began a linkage analysis of pure cerebellar ataxias in Japan and found a 19p-linked locus that turned out to be of SCA6. The remaining cases were linked to a 16q locus that turned out to be of SCA31.

In SCA31, MRI reveals almost pure cerebellar atrophy with preserved brainstem and cerebrum. The neuropathology of SCA31 is characterized by a peculiar halo-like amorphous material around degenerating Purkinje cells (PCs). The mutation is a complex penta-nucleotide repeat containing (TGGAA)n, (TAGAA)n and (TAAAA)n inserted in an intron shared by two different genes, BEAN and TK2, transcribed in mutually opposite directions. The transcripts create RNA foci in the SCA31 PC nuclei, though their pathogenic significance is unknown. In order to clarify its pathogenesis, we established cultured cell models with these repeat insertions. We found that only the nucleotide sequences containing (UGGAA)n, corresponding to the mutation transcribed in BEAN-direction, formed RNA foci and showed significant toxicity revealed by LDH and MTS assays, whereas other repeats did not. We also demonstrated that serine/arginine-rich splicing factor 1 (SFRS1), the splicing factor essential for any living cell and binds with (UGGAA)n in vitro, co-localized with RNA foci. In human SCA31 cerebella, the RNA foci were more in the morphologically preserved PCs than those in atrophic PCs. According to these findings, it is suggested the formation of RNA foci containing (UGGAA)n may be a hallmark of the SCA31 neurodegeneration, which potentially affects the nuclear SFRS1 level. SCA31 is considered one of a growing number of neuromuscular diseases with RNA-mediated gain-of-function mechanism such as myotonic dystrophies type 1 & 2, SCA8, SCA10 and fragile X-tremor ataxia syndrome. Further studies are necessary to find molecular targets for effective therapies of SCA31.

Based on our study of the SCA31 mutation in large European cohorts of SCA families in addition to a Japanese one, (TAAAA)n is the original pentanucleotide with polymorphic but small 8 to 21 repeats in both Caucasians and Japanese. However, large (TGGAA)n repeats associated with SCA31 and (TAGAA)n are exclusively found in Japanese whereas (TACAA)n, (GAAAA)n, (TAACA)n and (TGAAA)n pure expansions exclusively in Caucasians'. There may be some evolutional mechanisms regarding the Japanese and Caucasian expansions at the SCA31 locus.

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ISP2012 Abstracts