Pathogenesis of polyglutamine diseases: Piecing together a complex molecular puzzle

作者：Esmeralda Villavicencio Gonzalez, Huda Y. Zoghbi · 发表于：The Journal of Experimental Medicine · 年份：2025 · DOI：10.1084/jem.20241336 · 被引用次数：4 · 研究领域：Genetic Neurodegenerative Diseases、Mitochondrial Function and Pathology、Metabolism and Genetic Disorders

Polyglutamine (polyQ) diseases, caused by a CAG repeat expansion encoding a glutamine tract in nine distinct proteins, present a complex molecular puzzle in which each piece contributes to neurodegeneration. While each of the causative proteins has a distinct function, the downstream consequences of polyQ toxicity are often similar, including protein accumulation, transcriptional dysregulation, somatic CAG repeat instability, disrupted energy homeostasis, compromised synaptic function, and selective neuronal death. This review summarizes emerging insights into how proteins with an expanded polyQ tract disrupt distinct cellular functions, and we examine a multitude of discoveries that are inspiring and reshaping novel therapeutic strategies.