Huntingtin (HTT) (HTT)

Huntingtin is a large, ubiquitous scaffold protein encoded by the HTT gene that is essential for embryonic development and normal neuronal survival (UniProt P42858). It plays a critical role in various cellular processes, including intracellular transport, transcriptional regulation, and synaptic signaling (NCBI Gene 3064). Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expansion of CAG repeats in the HTT gene, resulting in a mutant huntingtin (mHTT) protein with an abnormally long polyglutamine tract (PubMed: 23446353). This mutant protein undergoes misfolding and aggregation, leading to proteotoxic stress and the progressive loss of medium spiny neurons in the striatum. Current therapeutic approaches aim to lower the levels of mHTT using antisense oligonucleotides (e.g., Tominersen), RNA interference (e.g., AMT-130), or small molecule splicing modulators (e.g., PTC518) (ClinicalTrials.gov). A major challenge in drug development is achieving allele-specific silencing to preserve the essential functions of the wild-type huntingtin protein while eliminating the toxic mutant form (Nature Reviews Neurology, 2020). Additionally, monitoring efficacy involves measuring mHTT levels in the cerebrospinal fluid and tracking neurodegeneration via neurofilament light chain levels and brain imaging. Safety concerns include the potential for off-target effects and the risks associated with long-term suppression of the endogenous wild-type protein.

Other names

Huntingtin proteinIT15Interesting transcript 15HDHuntington disease protein

Antisense oligonucleotide-mediated mRNA degradation, RNA interference (RNAi) for gene silencing, and small molecule-induced splicing modulation to reduce protein expression.