Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.
Nature. 2013 Jun 20;498(7454):325-331. doi: 10.1038/nature12204. Epub 2013 May 29.
Many neurodegenerative disorders, such as Alzheimer's, Parkinson's and polyglutamine diseases, share a common pathogenic mechanism: the abnormal accumulation of disease-causing proteins, due to either the mutant protein's resistance to degradation or overexpression of the wild-type protein. We have developed a strategy to identify therapeutic entry points for such neurodegenerative disorders by screening for genetic networks that influence the levels of disease-driving proteins. We applied this approach, which integrates parallel cell-based and Drosophila genetic screens, to spinocerebellar ataxia type 1 (SCA1), a disease caused by expansion of a polyglutamine tract in ataxin 1 (ATXN1). Our approach revealed that downregulation of several components of the RAS-MAPK-MSK1 pathway decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice. Importantly, pharmacological inhibitors of components of this pathway also decrease ATXN1 levels, suggesting that these components represent new therapeutic targets in mitigating SCA1. Collectively, these data reveal new therapeutic entry points for SCA1 and provide a proof-of-principle for tackling other classes of intractable neurodegenerative diseases.
许多神经退行性疾病，如阿尔茨海默病、帕金森病和多聚谷氨酰胺疾病，都具有共同的致病机制：致病蛋白的异常积累，要么是由于突变蛋白的降解抗性，要么是由于野生型蛋白的过度表达。我们已经开发了一种通过筛选影响致病蛋白水平的遗传网络来识别此类神经退行性疾病治疗切入点的策略。我们应用了这种方法，该方法整合了平行的基于细胞和果蝇的遗传筛选，用于治疗脊髓小脑共济失调 1 型（SCA1），这是一种由 ATXN1 中多聚谷氨酰胺片段扩展引起的疾病。我们的方法表明，下调 RAS-MAPK-MSK1 途径的几个成分可降低 ATXN1 水平并抑制果蝇和小鼠中的神经退行性变。重要的是，该途径的成分的药理学抑制剂也可降低 ATXN1 水平，这表明这些成分代表了减轻 SCA1 的新治疗靶点。总的来说，这些数据为 SCA1 提供了新的治疗切入点，并为解决其他类别的难治性神经退行性疾病提供了原理验证。
