Huntingtin protein (HTT) (HTT)

Huntingtin (HTT) is a large, ubiquitous protein essential for embryonic development and various cellular processes, including vesicular transport, cytoskeletal organization, and transcriptional regulation [1]. In Huntington's disease (HD), a CAG trinucleotide repeat expansion in the HTT gene leads to the production of a mutant huntingtin (mHTT) protein with an abnormally long polyglutamine (polyQ) tract [2]. This mutation causes the protein to misfold and form toxic intracellular aggregates, which disrupt cellular homeostasis, impair autophagy, and lead to the progressive degeneration of neurons, particularly in the striatum and cortex [1, 2]. Therapeutic strategies primarily focus on "huntingtin lowering" by targeting HTT mRNA with antisense oligonucleotides (ASOs), RNA interference (RNAi), or small molecule splicing modulators to reduce the production of the toxic protein [3]. Other approaches include enhancing the clearance of existing aggregates or preventing their formation to mitigate neurotoxicity and slow disease progression [4].

Other names

Mutant huntingtinmHTTHuntingtin aggregatesPolyglutamine-expanded huntingtinIT15

Reduction of mutant huntingtin protein levels via antisense oligonucleotides, RNA interference, or small molecule splicing modulation to prevent aggregate formation and proteotoxicity.