Find HTT Products Interaction Network for HTT HTT Details

Related Pathways Huntington's Disease Signaling View All Pathways

Synonyms: AI256365, C430023I11RIK, HD, Hdh, HTT, HUNTINGTIN, IT15

Huntington Pathway

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by polyglutamine (polyQ) expansion in the huntingtin (htt) protein. It is a member of a class of inherited diseases defined by the presence of polyglutamine expansions. Symptoms include involuntary movement (chorea), personality changes and dementia with progression to death due to massive, but selective neuronal dysfunction in the striatum (medium spiny neurons (MSN)) and cerebral cortex. Symptoms of HD generally manifest in the third or fourth decade of life. The age of symptom on-set correlates with the extent of polyQ expansion.

Huntingtin is a ubiquitously expressed protein that possesses anti-apoptotic properties and in neural tissue appears to be involved with huntingtin-associated protein-1 (HAP1) and the p150(Glued) subunit of dynactin-dependent vesicular transport of brain-derived neurotrophic factor (BDNF) along microtubules. HTT is thought to be involved with neurotransmission, axonal transport, and neuronal positioning. Normal HTT may prevent apoptosis by binding the pro-apoptotic factor Hip-1. Normal HTT protein genes have up to 26 CAG (cytosine-adenine-guanine) tri-nucleotide repeats that code for the polyglutamine tract near the N-terminus of huntingtin (Htt). In HD individual, there are between 38 and 100 glutamine (CAG) coding repeats.

The pathogenesis of HD has been associated with both loss-of-function (loss of anti-apoptotic activity) and gain-of-function resulting from polyQ expansion (a predisposition) and subsequent proteolytic cleavage of mutated HTT. A dominant aspect is gain-of-function relates to proteolytic cleavage. Cleavage of mutant HTT by caspases, calpains or aspartic proteases generate polyQ fragments that aggregate more efficiently and are more toxic than the whole mutant HTT molecule. Formation of polyQ HTT fragments may be a rate-limiting step in HD pathogenesis. Phosphorylation of HTT by kinases such as Cdk5 (highly expressed in neurons) or Akt helps protect HTT from cleavage by caspases. Inhibition of dephosphorylation of polyQ expanded HTT by calcium activated calcineurin (PP-2B) also protects cells.

PolyQ expanded HTT does not bind the pro-apoptotic factor, Hip-1, efficiently. This loss-of-function may allow the formation of Hip-1:Hippi (Hip-1 protein interactor) heterodimers that recruit and facilitate the activation of caspase-8 and caspase-3 leading to apoptosis.