Ubiquitin-Proteasome Dysfunction in Huntington's Disease and Its Mechanistic Insights and Druggable Targets Across the Proteostasis Network

Abstract

Huntington's disease (HD) offers a particularly instructive, if sobering, window into what happens when a cell's protein-clearance machinery is asked to do more than it can bear. Background: the ubiquitin-proteasome system (UPS) is the principal route by which short-lived and misfolded proteins are removed from eukaryotic cells, and it becomes especially indispensable in the neuronal nucleus, which has no meaningful autophagic backup. In HD, an expanded polyglutamine tract within mutant huntingtin (mHTT) appears to overwhelm this system through several compounding routes rather than any single lesion. Methods: we synthesized findings from 37 primary and review sources addressing UPS biology, HD pathogenesis, and emerging degrader technologies, following a structured, reproducible literature-identification and thematic-extraction protocol comparable to a rapid systematic review. Sources were screened for relevance to proteasome structure and function, E3 ligase/deubiquitinase (DUB) biology in HD, post-translational modification (PTM) crosstalk, and targeted protein degradation (TPD). Results: the synthesis converges on a picture in which soluble mHTT oligomers allosterically lock the 20S proteasome gate, aggregation-prone fragments stall within the catalytic chamber, and ubiquitin itself becomes a limiting resource ("ubiquitin stress"). These defects are not uniform across the cell; the nucleus, the synapse (via the Ube3a-Arc-AMPA axis), and the outer mitochondrial membrane each fail through distinct, druggable mechanisms. Opposing E3 ligases (CHIP, TRIM37, WWP1) and a competitive tug-of-war between ubiquitination and SUMOylation further shape whether mHTT is cleared or stabilized. Conclusion: targeted protein degradation platforms, DUB inhibitors, and proteasome activators together sketch a plausible, if still preclinical, path toward restoring proteostasis in HD and related proteinopathies.