Among the age-dependent protein aggregation disorders, nine neurodegenerative diseases are caused by expansions of CAG repeats encoding polyglutamine (polyQ) tracts. We review the clinical, pathological, and biological features of these inherited disorders. We discuss insights into pathogenesis gleaned from studies of model systems and patients, highlighting work that informs efforts to develop effective therapies. An important conclusion from these analyses is that expanded CAG/polyQ domains are the primary drivers of neurodegeneration, with the biology of carrier proteins influencing disease-specific manifestations. Additionally, it has become apparent that CAG/polyQ repeat expansions produce neurodegeneration via multiple downstream mechanisms, involving both gain- and loss-of-function effects. This conclusion indicates that the likelihood of developing effective therapies targeting single nodes is reduced. The evaluation of treatments for premanifest disease will likely require new investigational approaches. We highlight the opportunities and challenges underlying ongoing work and provide recommendations related to the development of symptomatic and disease-modifying therapies and biomarkers that could inform future research.

中文翻译：

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聚谷氨酰胺在神经退行性疾病中重复。

在年龄依赖性蛋白质聚集疾病中，九种神经退行性疾病是由编码聚谷氨酰胺（polyQ）束的CAG重复序列的扩增引起的。我们回顾了这些遗传性疾病的临床，病理和生物学特征。我们讨论了从模型系统和患者研究中收集到的有关发病机理的见解，重点介绍了有助于开发有效疗法的工作。这些分析的重要结论是，扩展的CAG / polyQ结构域是神经退行性病变的主要驱动因素，并且载体蛋白的生物学特性会影响特定疾病的表现。另外，很明显，CAG / polyQ重复扩增通过多种下游机制产生神经变性，涉及功能的获得和丧失。该结论表明，开发针对单个结节的有效疗法的可能性降低了。评估预后疾病的治疗方法可能需要新的研究方法。我们重点介绍了正在进行的工作所面临的机遇和挑战，并提供了与有症状和疾病缓解疗法和生物标志物的开发相关的建议，这些信息可以为将来的研究提供参考。