Polyglutamine aggregate (PolyQ aggregate)

Polyglutamine (polyQ) aggregates are insoluble protein clusters characterized by the accumulation of misfolded proteins containing expanded glutamine tracts. These expansions arise from CAG trinucleotide repeat mutations in specific genes, such as HTT in Huntington's disease or ATXN genes in spinocerebellar ataxias (Fan et al., 2014, PubMed: 25034314). The aggregates and their precursor oligomers exert neurotoxicity by sequestering vital cellular components, disrupting the proteasome-ubiquitin system, and impairing mitochondrial function (Zheng et al., 2016, PubMed: 27563465). As a therapeutic target, polyQ aggregates are addressed through strategies aimed at reducing the production of the mutant protein, preventing the initial misfolding, or accelerating the degradation of existing inclusions (Banno et al., 2015, PubMed: 25681102). Current clinical efforts include the use of antisense oligonucleotides (ASOs) to lower mutant protein levels and small molecules designed to stabilize the native protein conformation or induce autophagy (Tabrizi et al., 2019, NEJM: 380:2307-2318). These interventions aim to restore cellular proteostasis and prevent the progressive neuronal loss characteristic of polyglutamine diseases.

Other names

PolyQ inclusionPolyglutamine-expanded protein aggregateCAG repeat expansion aggregatePolyQ fibril

Inhibition of protein aggregation, enhancement of autophagic clearance, and reduction of mutant protein synthesis via antisense oligonucleotides or RNA interference.