8.A.222. The Huntingtin (HTT) Family
Huntingtin (Huntington disease protein (HD protein) may play a role in microtubule-mediated transport or vesicle function. The N-terminus is myristoylated; the protein, of 3142 aas with as many as 19 TMSs, promotes the formation of autophagic vesicles. There are 5 cleavage sites, where cleavage is catalyzed by caspases 3 and 6. Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity (Atwal et al. 2007). The mutant Huntingtin protein colocalizes with AKAP8L in the nuclear matrix of Huntington disease neurons. It shuttles between the cytoplasm and the nucleus in a Ran GTPase-independent manner (Cornett et al. 2005). The neurodegenerative disorder is characterized by involuntary movements (chorea), general motor impairment, psychiatric disorders and dementia. Onset of the disease occurs usually in the third or fourth decade of life. Onset and clinical course depend on the degree of poly-Gln repeat expansion, longer expansions resulting in earlier onset and more severe clinical manifestations. Neuropathology of Huntington disease displays a distinctive pattern with loss of neurons, especially in the caudate and putamen.