Huntingtin exon 1 polyglutamine aggregates (mHTT aggregates)

Huntingtin exon 1 polyglutamine aggregates are pathological protein assemblies formed by the mutant huntingtin (mHTT) protein, which contains an abnormally long sequence of glutamine residues. These aggregates are a hallmark of Huntington's disease (HD), a fatal neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene. The expansion of the polyglutamine tract beyond a certain threshold (typically >36 repeats) leads to the misfolding of the N-terminal fragment of the huntingtin protein, resulting in the formation of toxic oligomers and insoluble fibrils. These aggregates disrupt various cellular processes, including axonal transport, mitochondrial function, and transcriptional regulation, ultimately leading to neuronal death, particularly in the striatum and cortex. Therapeutic strategies targeting these aggregates include small molecules that inhibit fibrillization, PROTACs that promote the degradation of mHTT, and antisense oligonucleotides (ASOs) or splicing modulators that reduce the production of the mutant protein. Monitoring these aggregates via cerebrospinal fluid assays or specialized PET imaging is critical for evaluating the efficacy of disease-modifying therapies.

Other names

Mutant huntingtin aggregatesmHTT fibrilsPolyQ aggregatesHuntingtin protein aggregatesHuntingtin exon 1 fragments

Inhibition of mutant huntingtin protein synthesis via antisense oligonucleotides or splicing modulators, promotion of protein degradation, and inhibition of polyglutamine aggregation.