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.

中文翻译：

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miR760 通过与其 5' 非翻译区相互作用来调节 ATXN1 水平。


识别与神经退行性疾病有关的剂量敏感基因的修饰因子对于发现新的遗传风险因素和潜在的治疗切入点至关重要。在本研究中，我们重点关注 Ataxin-1 ( ATXN1 )，这是一种与神经退行性疾病 1 型脊髓小脑共济失调 (SCA1) 相关的剂量敏感基因。虽然精确维持 ATXN1 水平对于预防疾病至关重要，但调节ATXN1表达的机制仍然很大程度上未知。我们证明ATXN1异常长的 5' 非翻译区 (5' UTR) 通过转录后机制负向调节其表达。根据最近的报道，microRNA (miRNA) 可以与 3' 和 5' UTR 相互作用来调节其靶基因，我们将 miR760 确定为负调节因子，它与ATXN1的 5' UTR 中的保守位点结合，诱导 RNA 降解和翻译抑制。我们发现，在小脑中递送表达腺相关病毒（AAV）的 miR760 可以降低体内 ATXN1 水平，并减轻 SCA1 小鼠模型的运动协调缺陷。这些发现为 ATXN1 水平的调节提供了新的见解，为 miRNA 通过 5'UTR 结合介导的基因调节提供了额外的证据，并提出了ATXN1位点中的非编码突变可能作为尚未发现的进行性共济失调的危险因素的可能性。