Huntingtins

Huntingtins are the protein products of the HTT gene in humans. The huntingtin protein is large and widely expressed, with highest levels in the brain during development. The canonical form is about 3,100 amino acids long and weighs roughly 340 kilodaltons, and the gene can produce multiple isoforms through alternative splicing. A defining feature is an N-terminal polyglutamine tract encoded by a CAG repeat, whose length varies among individuals.

Normal function of huntingtin involves a variety of cellular processes essential for neuronal health. It participates in vesicle transport along microtubules, endocytosis, autophagy, mitochondrial function, and transcriptional regulation. It interacts with numerous binding partners and contributes to synaptic transmission and neuronal development. While its precise roles are not fully understood, huntingtin is considered important for cellular quality control and survival, particularly in neurons.

Mutations and disease arise when the CAG repeat in HTT expands, producing an elongated polyglutamine tract in huntingtin. This mutant form tends to misfold and form intracellular aggregates, contributing to neuronal dysfunction. Huntington's disease is inherited in an autosomal dominant pattern. A higher number of CAG repeats generally correlates with earlier onset and more rapid progression, a phenomenon known as anticipation. Neurodegeneration predominantly affects the striatum and cortex, leading to motor impairment, cognitive decline, and psychiatric symptoms. Pathology includes neuronal loss, gliosis, protein inclusions, and widespread transcriptional dysregulation.

Research and therapy focus on slowing or stopping disease progression. No cure exists, and management is supportive. Therapeutic approaches include gene-silencing strategies to reduce huntingtin production, such as antisense oligonucleotides and RNA interference, as well as approaches targeting aggregation and proteostasis. As of 2024, several trials have explored huntingtin-lowering therapies, but no disease-modifying treatment has been approved.