The abnormal expansion of a polyglutamine (polyQ, GAG repeat) region in the amino terminus of the IT15 gene that encodes the normally cytoplasmic ~350kDa huntingtin (Htt) protein, is the molecular basis of HD.79 In normal individuals, the polyQ region of the htt gene is a GAG trinucleotide repeat length of 35. HD manifests when the GAG trinucleotide repeat length is larger than 40, with the age of onset of disease being inversely related to the size of the polyQ expansion such that the higher the number of repeats, the earlier the age of disease onset.78 However, the GAG trinucleotide repeat length is not predictive of the severity of symptoms or the rate of disease progression. At least one potential genetic modifier of disease is the glutamate receptor 6 (GluR6) subunit of the kainate receptor, suggesting that excitotoxicity may be involved in disease pathogenesis.80
The normal function of htt is unknown, but it may have a role in vesicle transport, clathrin-mediated endocytosis, postsynaptic signaling, and neuronal survival.81 HD results from a 'gain of function' in the mutant htt protein coupled with a loss of function of the wild-type protein. The processing of the htt protein appears central to disease pathophysiology. Mutant htt is enzymatically cleaved by caspases and calpains to generate small N-terminal fragments that exacerbate the development of intranuclear and cytoplasmic protein aggregates, also termed inclusions.82 The proteosome also appears to play a role in inclusion formation as an inhibitor of this enzyme complex. Lactacystin increases aggregate formation while overexpression of chaperone proteins, e.g., HSP70, involved in refolding of abnormal proteins, can rescue cells from htt-induced death. It is controversial whether aggregate formation is a toxic event. Aggregates sequester the protein mammalian target of rapamycin (mTOR) that is involved in the inhibition of autophagy that serves to clear htt fragments.81 Thus, aggregate formation could serve to stimulate enhanced clearance of htt fragments and act in a protective manner. The reason for selective vulnerability of GABAergic medium spiny interneurons in HD is unknown. Research has focused on the distribution and function of the 20 or so htt-associated proteins, e.g., HAP1, HIP 1 and 2.
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