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

Mutant huntingtin (mHTT) exon 1 is a fragment of the huntingtin protein containing an expanded polyglutamine (polyQ) tract, which is the primary driver of Huntington's disease (HD) pathogenesis [UniProt: P42858]. The expansion of CAG repeats in the HTT gene leads to the production of a protein that misfolds and forms various aggregation states, including soluble oligomers and insoluble fibrils, which are highly neurotoxic [PubMed: 31515304]. These mHTT exon 1 species disrupt critical cellular processes such as proteostasis, mitochondrial energy production, and axonal transport, leading to the progressive loss of neurons in the striatum and cortex. Current therapeutic development focuses on lowering mHTT levels through genetic approaches like antisense oligonucleotides (ASOs) or small molecule splicing modulators [Nature: 2021]. Additionally, research is exploring small molecules that can specifically inhibit the aggregation of polyQ-expanded fragments or promote their degradation to mitigate neurodegeneration. Monitoring mHTT in the cerebrospinal fluid and neurofilament light chain (NfL) in blood serves as essential biomarkers for assessing disease progression and treatment efficacy [Lancet Neurology: 2017].

Other names

mHTTMutant huntingtinPolyglutamine-expanded huntingtinHuntingtin exon 1 fragmentmHTT aggregatesPolyQ-expanded huntingtin

Therapeutic strategies include the use of antisense oligonucleotides (ASOs) and RNA interference (RNAi) to reduce HTT mRNA levels, small molecule splicing modulators to lower total or mutant HTT protein, and aggregation inhibitors designed to prevent the formation of toxic polyglutamine-expanded species or promote their clearance via autophagy [PubMed: 33414132, Nature Reviews Drug Discovery: 2019].