Mutant huntingtin (mHTT) exon 1 (mHTT exon 1)

Mutant huntingtin (mHTT) exon 1 refers to the N-terminal fragment of the huntingtin protein containing an abnormally expanded polyglutamine (polyQ) tract. This expansion, resulting from a CAG repeat mutation in the HTT gene, causes the protein to misfold and form toxic aggregates, which are the primary drivers of Huntington's disease (HD) pathogenesis (UniProt P42858; PubMed PMID: 31434658). The exon 1 fragment is particularly pathogenic because it is highly prone to forming amyloid-like fibrils and nuclear inclusions that disrupt essential cellular processes, including proteostasis, mitochondrial function, and axonal transport (PubMed PMID: 32103171). Therapeutic strategies targeting mHTT exon 1 focus on reducing its production through antisense oligonucleotides (ASOs) and splicing modulators or enhancing its clearance via autophagy-inducing small molecules (Roche, 2024; PTC Therapeutics, 2024). A significant challenge in drug development is achieving allele-specific targeting to reduce toxic mHTT while preserving the vital physiological functions of the wild-type huntingtin protein (Wave Life Sciences, 2024). Current clinical research is focused on determining whether lowering mHTT levels can safely slow or halt the progression of neurodegeneration in patients.

Other names

mHTTHuntingtin exon 1 fragmentIT15Huntingtin proteinPolyglutamine-expanded huntingtin

Antisense oligonucleotide-mediated mRNA degradation, splicing modulation to reduce protein expression, small molecule-mediated inhibition of translation, and autophagy induction to enhance protein clearance.