Journal Article

Identification of Splicing Regulatory Activity of ATXN1 and Its Associated Domains

Kato, Masahide, Yanaizu, Motoaki, Kino, Yoshihiro, Ohki, Ai, Aoki, Yoshitaka, Kubokawa, Arisa

2025

Overview

The expansion of the polyglutamine tract in ATXN1 contributes to the pathogenesis of SCA1. ATXN1 functions as a transcriptional regulator that interacts with multiple transcription factors, and transcriptional dysregulation has been observed in SCA1. In addition, splicing dysregulation has been identified in cells derived from SCA1 patients and model mouse tissues. Although ATXN1 binds to RNA and splicing factors, its direct involvement in pre-mRNA splicing remains unclear. Here, we demonstrate that ATXN1 regulates the alternative splicing of several minigenes. Using an Mbnl1 minigene, we found that neither expansion nor deletion of the polyglutamine tract affected ATXN1-mediated splicing regulation. Deletion analysis revealed that its splicing regulatory activity involves a central region of ATXN1, the AXH domain, and a nuclear localization signal in the C-terminal region. The AXH domain alone failed to exhibit splicing regulatory activity, whereas the central region demonstrated weak but significant splicing regulation. Full regulatory function required at least one of these regions, suggesting their redundant role in splicing modulation. Importantly, we newly identified the central region as mediating RNA binding. These findings suggest a novel role for ATXN1 in alternative splicing, providing new insights into the mechanisms underlying SCA1 pathogenesis.

• Publisher: MDPI AG,MDPI
• Subject: Alternative Splicing / Analysis / Animals / Ataxin / Ataxin-1 - chemistry / Ataxin-1 - genetics / Ataxin-1 - metabolism / ATXN1 / Disease / HEK293 Cells / Humans / Localization / Messenger RNA / Mice / Pathogenesis / Peptides - genetics / Peptides - metabolism / Phosphorylation / Plasmids / Polyglutamine / Protease inhibitors / Protein Domains / Proteins / RNA binding / RNA Splicing / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / spinocerebellar ataxia type 1 / Splicing factors / Transcription factors / Trinucleotide repeat diseases