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 Comparative

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by polyglutamine (polyQ) expansion in the huntingtin (htt) protein. 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 vesicular transport of brain-derived neurotrophic factor (BDNF) along microtubules. 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.

Mutant HTT polyQ fragments accumulate within the nucleus and may participate in early progression of neuropathology by interfering with specific elements of the gene transcription machinery. Mutant HTT fragments interact and may interfere with transcription factors such as p53, CREB, Sp1, mSina, and TATA-binding protein. Furthermore, HTT polyQ fragments affect a class of genes regulated by the histone acetylation and deacetylation cycle. Histone acetyltransferases is important for relaxing chromatin and allowing transcription of this class of genes. HTT polyQ fragments can bind acetyltransferases and interfere with this function.

Normal HTT can bind Huntingtin interacting protein-1 (Hip-1), a protein involved in clathrin-dependent endocytosis that recruits clathrin to phospholipid rich locations on the plasma membrane. When Hip-1 is not bound by HTT or another polyglutamine containing protein it can become pro-apoptotic. 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 allow the activation of caspase-8 and caspase-3 leading to apoptosis. Hip-1 also directly binds to caspase-9 and Apaf-1 leading to apoptosis.