the rate of progression. Mechanisms Huntingtin protein interacts with over 100 other proteins, and appears to have multiple functions. The behavior of the mutated protein (mHtt) is not completely understood, but it is toxic to certain cell types, particularly brain cells. Early damage is most evident in the subcortical basal ganglia, initially in the striatum, but as the disease progresses, other areas of the brain are also affected, including regions of the cerebral cortex. Early symptoms are attributable to functions of the striatum and its cortical connections—namely control over movement, mood, and higher cognitive function. DNA methylation also appears to be changed in HD. Huntingtin function Htt is expressed in all cells, with the highest concentrations found in the brain and testes, and moderate amounts in the liver, heart, and lungs. Its functions are unclear, but it does interact with proteins involved in transcription, cell signaling, and intracellular transporting. In animals genetically modified to exhibit HD, several functions of Htt have been identified. In these animals, Htt is important for embryonic development, as its absence is related to embryonic death. Caspase, an enzyme which plays a role in catalyzing apoptosis, is thought to be activated by the mutated gene through damaging the ubiquitin-protease system. It also acts as an antiapoptotic agent preventing programmed cell death and controls the production of brain-derived neurotrophic factor, a protein that protects neurons and regulates their creation during neurogenesis. Htt also facilitates synaptic vesicular transport and synaptic transmission, and controls neuronal gene transcription. If the expression of Htt is increased, brain cell survival is improved and the effects of mHtt are reduced, whereas when the expression of Htt is reduced, the resulting characteristics are more as seen in the presence of mHtt. Accordingly, the disease is thought not to be caused by inadequate production of Htt, but by a toxic gain-of-function of mHtt in the body. Cellular changes The toxic action of mHtt may manifest and produce the HD pathology through multiple cellular changes. In its mutant (polyglutamine expanded) form, the protein is more prone to cleavage that creates shorter fragments containing the polyglutamine expansion. These protein fragments have a propensity to undergo misfolding and aggregation, yielding fibrillar aggregates in which non-native polyglutamine β-strands from multiple proteins are bonded together by hydrogen bonds. These aggregates share the same fundamental cross-beta amyloid architecture seen in other protein deposition diseases . Over time, the aggregates accumulate to