miR760 regulates ATXN1 levels via interaction with its 5' untranslated region.

Abstract

Identifying modifiers of dosage-sensitive genes involved in neurodegenerative disorders is imperative to discover novel genetic risk factors and potential therapeutic entry points. In this study, we focus on Ataxin-1 (ATXN1), a dosage-sensitive gene involved in the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1). While the precise maintenance of ATXN1 levels is essential to prevent disease, the mechanisms that regulate ATXN1 expression remain largely unknown. We demonstrate that ATXN1's unusually long 5' untranslated region (5' UTR) negatively regulates its expression via posttranscriptional mechanisms. Based on recent reports that microRNAs (miRNAs) can interact with both 3' and 5' UTRs to regulate their target genes, we identify miR760 as a negative regulator that binds to a conserved site in ATXN1's 5' UTR to induce RNA degradation and translational inhibition. We found that delivery of Adeno-associated virus (AAV)-expressing miR760 in the cerebellum reduces ATXN1 levels in vivo and mitigates motor coordination deficits in a mouse model of SCA1. These findings provide new insights into the regulation of ATXN1 levels, present additional evidence for miRNA-mediated gene regulation via 5' UTR binding, and raise the possibility that noncoding mutations in the ATXN1 locus may act as risk factors for yet to be discovered progressive ataxias.

• Authors: Larissa Nitschke, Ambika Tewari, Stephanie L Coffin, Eder Xhako, Kaifang Pang, Vincenzo A Gennarino, Jennifer L Johnson, Francisco A Blanco, Zhandong Liu, Huda Y Zoghbi
• Journal: Genes & development (Genes Dev) Vol. 34 Issue 17-18 Pg. 1147-1160 (09 01 2020) ISSN: 1549-5477 [Electronic] United States
• PMID: 32763910 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Nitschke et al.; Published by Cold Spring Harbor Laboratory Press.

Chemical References

• 5' Untranslated Regions
• Ataxin-1
• MIRN760 microRNA, human
• MicroRNAs

Topics

• 5' Untranslated Regions (genetics)
• Animals
• Ataxin-1 (genetics, metabolism)
• Cell Line
• Gene Expression Regulation (genetics)
• Humans
• Mice
• Mice, Inbred C57BL
• MicroRNAs (genetics, metabolism)
• Mutation
• Risk Factors
• Spinocerebellar Ataxias (genetics, physiopathology)