Pathomechanistic studies of neurodegenerative diseases have documented the toxic effects of mutant protein expression, misfolding, and aggregation. However, alterations in the expression of the corresponding wild-type (WT) gene, due to either variations in copy number or transcriptional regulation, have also been linked to Alzheimer's and Parkinson's diseases. Another striking example of this mutant and WT duality is spinocerebellar ataxia type 1 (SCA1) caused by an ATXN1 polyglutamine protein, although subtle variations in WT AXTN1 levels also lead to ataxia. In this issue of Genes & Development, Nitschke and colleagues (pp. 1147–1160) delve into posttranscriptional events that fine-tune ATXN1 expression and uncover a key role for 5′ untranslated region (5′ UTR)–miR760 interactions. Thus, this study not only provides significant insights into the complexities of modulating the expression of a dosage-sensitive gene but also highlights the critical importance of identifying noncoding polymorphisms as disease risk factors.

中文翻译：

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通过miR控制UTteR：微调ATXN1水平以预防共济失调。

神经退行性疾病的病理机制研究已证明突变蛋白表达，错误折叠和聚集的毒性作用。然而，由于拷贝数或转录调控的变化，相应的野生型（WT）基因表达的改变也与阿尔茨海默氏病和帕金森氏病有关。这种突变和WT对偶的另一个引人注目的例子是由ATXN1多谷氨酰胺蛋白引起的1型小脑共济失调（SCA1），尽管WT AXTN1水平的细微变化也导致了共济失调。在本期《基因与发展》中，Nitschke及其同事（第1147-1160页）深入研究了转录后事件，这些事件可微调ATXN1表达并揭示5'非翻译区（5'UTR）-miR760相互作用的关键作用。因此，这项研究不仅为调节剂量敏感性基因表达的复杂性提供了重要见解，而且还突出了将非编码多态性鉴定为疾病危险因素的至关重要性。