Ubiquitin-Dependent Protein Quality Control in Polyglutamine Diseases

Polyglutamine diseases comprise a family of nine age-dependent disorders caused by CAG triplet-repeat expansions that produce misfolded proteins with elongated glutamine tracts. Although these diseases share proteotoxic stress and engagement of protein quality control pathways as responses to their presence and disruptive activities, they differ in protein context, normal function, localization, interactomes and selective vulnerability. Here, we review how expanded polyglutamine proteins engage ubiquitin-dependent protein quality control across Huntington's disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, and spinocerebellar ataxias 1, 2, 3, 6, 7 and 17. Rather than treating protein quality control as a uniform response, we emphasize pathway selectivity. A central theme arises across these diseases: mutant polyglutamine proteins are recognized by ubiquitin-related machinery, but recognition does not necessarily produce productive degradation. Instead, disease-specific outcomes are shaped by tissue context, subcellular localization, aggregate state, disease protein fragmentation, normal protein function, compensatory pathway activation and local proteostasis capacity over time. The information synthesized in this review may help the field develop a more comparative and granular understanding of processes and pathways that are shared or divergent among polyglutamine diseases and may also inform more targeted therapeutic strategies for this family of incurable disorders.