Author:
Nitschke Larissa,Tewari Ambika,Coffin Stephanie L.,Xhako Eder,Pang Kaifang,Gennarino Vincenzo A.,Johnson Jennifer L.,Blanco Francisco A.,Liu Zhandong,Zoghbi Huda Y.
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.
Funder
National Institute of Neurological Disorders and Stroke
Howard Hughes Medical Institute
Baylor Research Advocates for Student Scientists
National Ataxia Foundation
Intellectual and Developmental Disabilities Research Center
National Institute of Child Health and Human Development
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
25 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献