Mutant huntingtin protein aggregates (mHTT aggregates)

Mutant huntingtin protein aggregates are the primary pathological hallmark of Huntington's disease (HD), an autosomal dominant neurodegenerative disorder (NIH, 2023). These aggregates form due to a CAG trinucleotide repeat expansion in the HTT gene, which encodes an elongated polyglutamine (polyQ) tract in the huntingtin protein (UniProt P42858). The expanded polyQ tract causes the protein to misfold into toxic oligomers and eventually into large, insoluble intracellular inclusions that sequester essential cellular components and proteostasis machinery (PubMed PMID: 31034602). These aggregates interfere with critical biological functions such as axonal transport, proteasome activity, and mitochondrial energy production, leading to progressive neuronal loss particularly in the striatum and cortex (Nature Reviews Neurology, 2017). Therapeutic interventions currently under investigation include antisense oligonucleotides (ASOs) like Tominersen, which aim to reduce mHTT synthesis, and small molecules designed to enhance the clearance of aggregates via the autophagy-lysosome pathway (PubMed PMID: 32814900). Accurate quantification of these aggregates in the central nervous system remains a key challenge for monitoring disease progression and therapeutic response in clinical settings.

Other names

Mutant huntingtin inclusionsmHTT fibrilsPolyglutamine aggregatesHuntingtin protein aggregatesmHTT oligomersHuntingtin inclusions

Reduction of mutant huntingtin protein synthesis via mRNA degradation or splicing modulation, enhancement of protein clearance via autophagy, and inhibition of protein aggregation or fibrillization.