Huntingtin

Huntingtin (Htt) is a human protein encoded by the HTT gene, also known as IT15 ("interesting transcript 15"). Pathogenic expansions in HTT (disease-causing repeat length increases) cause Huntington's disease (HD), and the protein has also been implicated in mechanisms of long-term memory storage.

HTT is expressed in many tissues, with the highest levels in the brain. Expression is developmentally regulated and required for embryogenesis. Huntingtin normally consists of 3,144 amino acids and has a predicted mass of ~350 kDa, depending on the length of its polyglutamine tract. Polymorphisms in HTT alter the number of glutamine residues: the wild-type allele encodes 6–35 repeats, whereas pathogenic expansions in HD exceed 36, with severe juvenile cases reaching ~250 repeats. The name huntingtin reflects this association with disease; IT15 was its earlier designation.

The molecular functions of huntingtin are not fully defined, but the protein is essential for neuronal survival and development. It is thought to contribute to intracellular signaling pathways, axonal transport, and vesicle trafficking, as well as to mediate protein–protein interactions. Huntingtin has also been shown to exert protective effects against apoptosis. Experimental disruption of HTT in model organisms results in embryonic lethality, underscoring its critical role in development. Expanded polyglutamine tracts in huntingtin cause toxic gain-of-function effects leading to Huntington's disease, an autosomal dominant neurodegenerative disease. The pathogenic protein aggregates in neurons, disrupting cellular processes and ultimately causing cell death.