huntingtin

Huntingtin is a large cytoplasmic and nuclear protein encoded by the HTT gene. The HTT gene is located on chromosome 4 (4p16.3) and encodes a protein of roughly 3,100 amino acids. The normal huntingtin protein is widely expressed, with highest levels in the brain, and it participates in numerous cellular processes including vesicular transport, endocytosis, autophagy, transcriptional regulation, and neuronal survival. It supports development and synaptic function, and knockout studies in animals indicate a critical, essential role for the protein.

Huntington's disease arises from an expansion of a CAG trinucleotide repeat within HTT, encoding an expanded polyglutamine tract in huntingtin. Healthy individuals typically have fewer than about 35 repeats; disease-associated expansions are usually more than 36 repeats, with longer repeats often linked to earlier onset (anticipation). The mutant protein tends to misfold and form aggregates, producing toxic effects that disrupt multiple cellular pathways. Pathogenic mechanisms include transcriptional dysregulation, mitochondrial dysfunction, impaired axonal transport, and synaptic degeneration, particularly in the striatum and cortex.

The condition is inherited in an autosomal dominant pattern. Onset commonly occurs in mid-adulthood but varies, and the disease progresses over 10–25 years. There is no cure; management focuses on alleviating symptoms and providing supportive care. In addition to symptomatic treatments for movement, mood, and cognition, research is exploring disease-modifying approaches, such as gene-silencing strategies to lower huntingtin expression, in clinical trials.