Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 May 25:15:648133.
doi: 10.3389/fnins.2021.648133. eCollection 2021.

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

Taro Ishiguro  1 , Yoshitaka Nagai  2 , Kinya Ishikawa  1   3
Affiliations
Review

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

Taro Ishiguro et al. Front Neurosci. .

Abstract

Spinocerebellar ataxia type 31 (SCA31) is a progressive neurodegenerative disease characterized by degeneration of Purkinje cells in the cerebellum. Its genetic cause is a 2.5- to 3.8-kb-long complex pentanucleotide repeat insertion containing (TGGAA)n, (TAGAA)n, (TAAAA)n, and (TAAAATAGAA)n located in an intron shared by two different genes: brain expressed associated with NEDD4-1 (BEAN1) and thymidine kinase 2 (TK2). Among these repeat sequences, (TGGAA)n repeat was the only sequence segregating with SCA31, which strongly suggests its pathogenicity. In SCA31 patient brains, the mutant BEAN1 transcript containing expanded UGGAA repeats (UGGAAexp) was found to form abnormal RNA structures called RNA foci in cerebellar Purkinje cell nuclei. In addition, the deposition of pentapeptide repeat (PPR) proteins, poly(Trp-Asn-Gly-Met-Glu), translated from UGGAAexp RNA, was detected in the cytoplasm of Purkinje cells. To uncover the pathogenesis of UGGAAexp in SCA31, we generated Drosophila models of SCA31 expressing UGGAAexp RNA. The toxicity of UGGAAexp depended on its length and expression level, which was accompanied by the accumulation of RNA foci and translation of repeat-associated PPR proteins in Drosophila, consistent with the observation in SCA31 patient brains. We also revealed that TDP-43, FUS, and hnRNPA2B1, motor neuron disease-linked RNA-binding proteins bound to UGGAAexp RNA, act as RNA chaperones to regulate the formation of RNA foci and repeat-associated translation. Further research on the role of RNA-binding proteins as RNA chaperones may also provide a novel therapeutic strategy for other microsatellite repeat expansion diseases besides SCA31.

Keywords: RAN translation; RBP; RNA chaperone; RNA foci; SCA31; TDP-43; microsatellite repeat.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic diagram of PPR proteins. Amino acids are shown as single letters. Translation of the UGGAA repeat in all frames would result in the production of an identical PPR protein, poly-WNGME. Asterisk (*) indicates a stop codon in the sequence surrounding the UGGAA repeat. Note that the TGGAA repetitive sequence itself includes an AUG translation–initiation codon, and both the TAAAA and the TAGAA sequences flanking the TGGAA repetitive sequence include UAA and UAG translation stop codons. AUG codons shown in orange stand for start, and blue color codons stand for stop in repeat sequence in a BEAN1 transcript. SCA31 shows slowly progressive cerebellar ataxia and MRI-proven cerebellar atrophy. Purkinje cells are primarily affected showing characteristic degenerative changes. Abnormal RNA aggregates called RNA foci are occasionally detected in Purkinje cell nuclei by fluorescent in situ hybridization (FISH) using probes against the (UGGAA)n-containing transcripts (Ishiguro et al., 2017). Furthermore, TDP-43 clearly colocalized with RNA foci in human SCA31 Purkinje cells. PPR proteins were also detected in cell bodies and dendrites of SCA31 Purkinje cells (arrows) (Ishiguro et al., 2017). Possible hairpin structures in UGGAA repeat containing internal loop with three consecutive G-A, G-G, and A-G mismatch base pairs (shown in red) (Shibata et al., 2021).
FIGURE 2
FIGURE 2
In DM1, MBNL1 promotes nuclear retention of expanded CUG repeat RNA and RNA foci formation, resulting in repression of RAN translation from CUG repeat RNA. In addition to MBNL1, DDX5, and DDX6 are also involved in DM1. DDX5 leads to degradation of the expanded CUG and CCUG RNAs and suppresses RNA foci formation. In C9orf72-ALS/FTD, hnRNPA3 reduced repeat RNA expression levels leading to decreasing RNA foci formation and DPR deposition. The helicase DDX3X, which unwinds (or relaxes) RNA, suppresses RAN translation and toxicity.
FIGURE 3
FIGURE 3
TDP-43 has RNA chaperone activity, structurally altering RNAs and affects UGGAA repeat-mediated toxicity and RNA foci formation in SCA31. FUS and hnRNPA2B1 also bind do UGGAA repetitive RNA and act as RNA chaperones, suppressing RNA foci formation and PPR translation. Small-molecule binders to UGGAA repeat inhibit RNA foci formation.
FIGURE 4
FIGURE 4
Proposed pathogenic mechanisms in SCA31. BEAN1 transcripts including expanded UGGAA repeat and TK2 transcripts including expanded UUCCA repeat may cause neurodegeneration by RNA foci formation and RAN translation. Further investigation will clarify whether TK2 transcripts with the expanded repeat behave in a similar manner.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Banez-Coronel M., Ranum L. P. W. (2019). Repeat-associated non-AUG (RAN) translation: insights from pathology. Lab. Investig. 99 929–942. 10.1038/s41374-019-0241-x - DOI - PMC - PubMed
    1. Basri R., Yabe I., Soma H., Sasaki H. (2007). Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families. J. Hum. Genet. 52 848–855. 10.1007/s10038-007-0182-x - DOI - PubMed
    1. Cheng W., Wang S., Zhang Z., Morgens D. W., Hayes L. R., Lee S., et al. (2019). CRISPR-Cas9 Screens Identify the RNA Helicase DDX3X as a Repressor of C9ORF72 (GGGGCC)n repeat-associated non-AUG translation. Neuron 104 885–898.e8. 10.1016/j.neuron.2019.09.003 - DOI - PMC - PubMed
    1. Courchaine E. M., Lu A., Neugebauer K. M. (2016). Droplet organelles? EMBO J. 35 1603–1612. 10.15252/embj.201593517 - DOI - PMC - PubMed
    1. Eymery A., Souchier C., Vourc’h C., Jolly C. (2010). Heat shock factor 1 binds to and transcribes satellite II and III sequences at several pericentromeric regions in heat-shocked cells. Exp. Cell Res. 316 1845–1855. 10.1016/j.yexcr.2010.02.002 - DOI - PubMed

LinkOut - more resources