<unk>  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<unk> .<unk>  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<unk> , 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 A microscope image of a neuron with an inclusion body (stained orange) caused by<unk> , image width 250 µm The toxic action of mHtt may manifest and produce the<unk>  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 form inclusion bodies within cells, ultimately interfering with neuronal function. Inclusion bodies have been found in both the cell nucleus and cytoplasm. Inclusion bodies in cells of the brain are one of the earliest pathological changes, and some experiments have found that they can be toxic for the cell, but other experiments have shown that they may form as part of the body's defense mechanism and help protect cells. Several pathways by which mHtt may cause cell death have been identified. These include effects on chaperone proteins, which help fold proteins and remove misfolded ones; interactions with caspases, which play a role in the process of removing cells; the toxic effects of glutamine on nerve cells; impairment of energy production within cells; and effects on the expression of genes. Mutant<unk>  protein has been found to play a key role in mitochondrial dysfunction. The impairment of mitochondrial electron transport can result in higher levels of oxidative stress and release of reactive oxygen species. Glutamine is known to be excitotoxic when present in large amounts, that can cause damage to numerous cellular structures. Excessive glutamine is not found in<unk> , but the interactions of the altered<unk>  protein with numerous proteins in neurons lead to an increased vulnerability to glutamine. The increased vulnerability is thought to result in excitotoxic effects from normal glutamine levels. Macroscopic changes The area of the brain most damaged in early<unk>  is the dorsal striatum made up of the caudate nucleus and the putamen. Initially, damage to the brain is regionally specific with the dorsal striatum in the subcortical basal ganglia being primarily affected, followed later by cortical involvement in all areas. Other areas of the basal ganglia affected include the substantia nigra; cortical involvement includes cortical layers 3, 5, and 6; also evident is involvement of the hippocampus, Purkinje cells in the cerebellum, lateral tuberal nuclei of the hypothalamus and parts of the thalamus. These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells. Striatal medium spiny neurons are the most vulnerable, particularly ones with projections towards the external globus pallidus, with interneurons and spiny cells projecting to the internal globus pallidus being less affected.<unk>  also causes an abnormal increase in astrocytes and activation of the brain's immune cells, microglia. The basal ganglia play a key role in movement and behavior control. Their functions are not fully understood, but theories propose that they are part of the cognitive executive system and the motor circuit. The basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in an awkward start to motion or motions to be unintentionally initiated, or a motion to be halted before, or beyond, its intended completion. The accumulating damage to this area causes the characteristic erratic movements associated with<unk>  known as chorea, a dyskinesia. Because of the basal ganglia's inability to inhibit movements, individuals affected by it inevitably experience a reduced ability to produce speech and swallow foods and liquids (dysphagia). Transcriptional dysregulation CREB-binding protein (CBP), a transcriptional coregulator, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of genes for survival pathways. Furthermore, the amino acids that form CBP include a strip of 18 glutamines. Thus, the glutamines on CBP interact directly with the increased numbers of glutamine on the HTT chain and CBP gets pulled away from its typical location next to the nucleus. Specifically, CBP contains an acetyltransferase domain to which HTT binds through its polyglutamine-containing domain. Autopsied brains of those who had<unk>  also have been found to have incredibly reduced amounts of CBP. In addition, when CBP is overexpressed, polyglutamine-induced death is diminished, further demonstrating that CBP plays an important role in<unk>  and neurons in general.
Huntington's disease
Wilson's disease
Stratton Parker syndrome
Paraneoplastic syndrome
Sandhoff disease
Lupus
X-linked dystonia parkinsonism
Benign hereditary chorea