Molecular Mechanisms and Future Therapeutics for Spinocerebellar Ataxia Type 31 (SCA31)

Abstract

Spinocerebellar ataxia type 31 (SCA31) is one of the autosomal-dominant neurodegenerative disorders that shows progressive cerebellar ataxia as a cardinal symptom. This disease is caused by a 2.5-to 3.8-kb-long complex pentanucleotide repeat containing (TGGAA) n , (TAGAA) n , (TAAAA) n , and (TAAAATAGAA) n in an intron of the gene called BEAN1 (brain expressed, associated with Nedd4). By comparing various pentanucleotide repeats in this particular locus among control Japanese and Caucasian populations, it was found that (TGGAA) n was the only sequence segregating with SCA31, strongly suggesting the pathogenicity of (TGGAA) n . The complex repeat also lies in an intron of another gene, TK2 (thymidine kinase 2), which is transcribed in the opposite direction, indicating that the complex repeat is bi-directionally transcribed as noncoding repeats. In SCA31 human brains, (UGGAA) n , the BEAN1 transcript of SCA31 mutation was found to form abnormal RNA structures called RNA foci in cerebellar Purkinje cell nuclei. Subsequent RNA pulldown analysis disclosed that (UGGAA) n binds to RNA-binding proteins TDP-43, FUS, and hnRNP A2/B1. In fact, TDP-43 was found to co-localize with RNA foci in human SCA31 Purkinje cells. To dissect the pathogenesis of (UGGAA) n in SCA31, we generated transgenic fly models of SCA31 by overexpressing SCA31 complex pentanucleotide repeats in Drosophila. We found that the toxicity of (UGGAA) n is length-and expression level-dependent, and it was dampened by co-expressing TDP-43, FUS, and hnRNP A2/B1. Further investigation revealed that TDP-43 ameliorates (UGGAA) n toxicity by directly fixing the abnormal structure of (UGGAA) n . This led us to propose that TDP-43 acts as an RNA chaperone against toxic (UGGAA) n . Further research on the role of RNA-binding proteins as RNA chaperones may provide a novel therapeutic strategy for SCA31.

Repeat Expansion Disorders: Mechanisms and Therapeutics

“…As described by Drs. Ishikawa and Nagai, an emerging mechanism of RNA toxicity is apparent for this disease [30].…”

Insight Into Spinocerebellar Ataxia Type 31 (SCA31) From Drosophila Model

“…SCA31 is one of the autosomal-dominant neurodegenerative disorders showing a relatively pure cerebellar form of ataxia. It is typically a disease of late adulthood, with onset peaking between 60 and 65 years of age ( Nagaoka et al, 2000 ; Sato et al, 2009 ; Nakamura et al, 2017 ; Ishikawa and Nagai, 2019 ). SCA31 is a common ataxia in Japan ( Onodera, 2006 ; Ouyang et al, 2006 ; Basri et al, 2007 ; Hayashi et al, 2007 ; Nozaki et al, 2007 ; Yoshida et al, 2009 ), whereas it is very rare in surrounding parts of Asia such as Korea, Taiwan, and China ( Lee et al, 2007 , 2012 ; Ouyang et al, 2012 ; Pedroso et al, 2015 ) and extremely rare in Caucasian populations ( Ishikawa et al, 2011 ).…”

Repeat RNA expansion disorders of the nervous system: post-transcriptional mechanisms and therapeutic strategies

“…Transcripts of repeat rich RNA can form dynamic aggregates that disrupt cellular function, often on a multisystem level, by sequestering RBPs and other essential proteins from native locations (Zhang and Ashizawa 2017). These RNA foci have been observed in a variety of MRE disorders, including FXTAS, C9orf72-ALS/FTD, DM1, DM2, FECD, HD, HDL2, SBMA, SCA-3, À8, À10, À31, and À36 (Rohilla and Gagnon 2017; Gendron and Petrucelli 2018; Ishikawa and Nagai 2019;Matthaei et al 2019;Nussbacher et al 2019;Paulson 2018;Swinnen et al 2020). The specific size, number, subcellular localization, and composition of pathogenic ribonucleoprotein foci may vary across and within MRE disorders, likely contributing to varying degrees of impairment to neuronal RNA processing, splicing, transport, or translation, gene regulatory processes critical for healthy neuronal and cognitive function (Markmiller et al 2018).…”

“…While many advances have been made in understanding key neuropathological mechanisms underlying various MRE disorders, there is still a surprising dearth of clinically approved therapies targeting these mechanisms. Indeed, while most approved treatments for MRE disorders provide only limited symptomatic amelioration, there are currently several therapeutic strategies under preclinical investigation that target the underlying pathology of MRE disorders ( Dickey and La Spada 2018 ; Egorova and Bezprozvanny 2019 ; Ishikawa and Nagai 2019 ; Panza et al 2020 ). By targeting the underlying pathology, researchers aim to prevent the spectrum of disease phenotypes associated with a specific neuropathological MRE ( Rohilla and Gagnon 2017 ).…”