Mutant huntingtin (mHTT) (mHTT)

Mutant huntingtin (mHTT) is the pathogenic form of the huntingtin protein, resulting from a CAG trinucleotide repeat expansion in the HTT gene (UniProt P42858). While the wild-type huntingtin protein is essential for neuronal development, synaptic function, and axonal transport, the mutant variant undergoes misfolding and forms toxic intracellular aggregates (NIH/NINDS). These aggregates disrupt various cellular processes, including mitochondrial function, proteasomal degradation, and transcriptional regulation, leading to the progressive loss of medium spiny neurons in the striatum (PubMed: PMC6524711). Huntington's disease is the primary clinical manifestation of this mutation, characterized by motor, cognitive, and psychiatric decline. Therapeutic strategies focus on "huntingtin lowering" to reduce the production of the toxic protein using antisense oligonucleotides (ASOs) like Tominersen or small molecule splicing modulators like PTC518 (Tabrizi et al., NEJM 2019; PTC Therapeutics). A critical challenge in drug development is achieving allele-specific targeting, as seen with WVE-003, to preserve the beneficial functions of wild-type huntingtin while eliminating the mutant form (Wave Life Sciences). Monitoring mHTT levels in the cerebrospinal fluid and neurofilament light chain (NfL) as a marker of neurodegeneration are essential for assessing treatment efficacy (PubMed: PMC7365210).

Other names

Mutant HTTHuntington disease proteinIT15mHTT proteinMutant huntingtin gene

Reduction of mutant huntingtin protein levels through antisense oligonucleotides (ASOs), RNA interference (RNAi), or small molecule splicing modulators to prevent toxic gain-of-function effects.