Pathogenesis of polyQ diseases. PolyQ pathogenesis involves the interplay of several disrupted cellular processes. The mutated gene is transcribed, producing RNA that can misfold, undergo aberrant splicing, and exert RNA toxicity. After translation takes place in the cytoplasm, the mutant protein is often cleaved by proteolytic enzymes into aggregation-prone fragments. Many aberrantly spliced transcripts are also translated into fragments that aggregate readily. Both full-length and fragmented proteins that contain a nuclear localization signal translocate into the nucleus, where they form toxic soluble oligomers and, eventually, insoluble aggregates. These aggregates deplete the host protein and other essential cellular factors from their native functions, leading to transcriptional dysregulation and widespread dysfunction. Additional cellular pathways including endoplasmic reticulum dynamics, mitochondrial bioenergetic pathways, protein clearance, and calcium signaling are disrupted. Moreover, the CAG tract is prone to somatic expansion due to failed MMR, resulting in the progressive lengthening of the tract and exacerbation of toxicity (created in BioRender, https://BioRender.com/r78karc).