2025/10/01 by Esmeralda Villavicencio Gonzalez, Huda Y. Zoghbi · 1 voice
Neuroscience · Biochemistry, Genetics and Molecular Biology · #Genetic Neurodegenerative Diseases #Mitochondrial Function and Pathology #Metabolism and Genetic Disorders
paper · doi:10.1084/jem.20241336
openalex publication_date 2025/10/01 · openalex created_date 2025/10/24 · openalex updated_date 2026/07/28
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.