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Huntington's disease is a neurodegenerative disease characterized by cognitive decline and motor dysfunction. It is a genetic disorder which results in the production of mutant huntingtin protein (mHtt). This protein aggregates in the cell cytoplasm and nucleus, affecting cellular function.
The ubiquitously expressed huntingtin protein is encoded by the Huntingtin gene. Huntington's disease is classified as a trinucleotide repeat disorder because it arises from the repetition of a three base sequence (CAG). These expanded repeats generate a series of glutamine residues, also known as a polyglutamine tract (polyQ). If the number of CAG codons exceeds a set threshold (35 repeats), the protein encoded by the altered gene (mHtt) is different to the normal protein product (Htt). This is particularly important when considering the genetic basis of Huntington's disease, as the number of repeats is not fixed and may vary between generations. The number may also increase upon cell division, and the length of the repeat is correlated with the age of onset of disease. Huntington's disease exhibits high penetrance, meaning that those who inherit the mutant allele will have the disease. The prevalence of Huntington's disease is approximately 5-10 per 100,000 people. Disease onset normally occurs between the ages of 35 and 50.
Huntingtin protein is cleaved within the N-terminal region by calpains, a process to which it is more susceptible as the length of the polyQ tract increases. Caspases have also been linked to the proteolysis of htt. The nature of this cleavage is of particular interest, since the cleavage products combine with other proteins to form inclusion bodies, aggregates in the neuronal cytoplasm and nuclei. These aggregates can cause proteasome dysfunction and transcriptional dysregulation, and gradually impede neurotransmission to the extent that neurotransmitter vesicles cannot move within the cytoskeleton. In addition to vesicular movement, mHtt also impairs mitochondrial trafficking. Neuronal dysfunction and/or death results, and the role of autophagy in the breakdown of these aggregates becomes even more emphasized; debate over the neuroprotective capacity of these aggregates means that the precise role of autophagy in Huntington's disease is yet to be fully characterized. Mutations at the calpain cleavage sites prevent the aggregation and toxicity of Htt protein; furthermore, proteolysis of mHtt by caspase-6 is also linked to neuronal dysfunction and neurodegeneration.
Huntington's disease primarily affects striatal medium spiny neurons (MSNs), neurons which receive both glutamate signals from the cortex and dopamine signals from the substantia nigra. A long-standing hypothesis postulates that high levels of excitatory neurotransmitters and/or activation of glutamate receptors (in particular the NMDA receptor) sensitize MSNs to cytotoxic cell death. Mutant htt is thought to decrease the expression of glutamate transporters and enhance the activity and toxicity of NMDA receptors (in particular NR1 and NR2B), thus causing striatal degeneration. A combination of glutamatergic afferents and unique NMDA receptor subtype composition in medium spiny neurons could be what confers their vulnerability to degeneration in Huntington's disease. Modifying the release of glutamate or dopamine is also shown to alter Huntington's disease pathology: for example, administration of L-DOPA or knockout of the dopamine transporter, both of which increase dopamine levels, increases loss of MSNs; attenuation of glutamate activity helps restore MSN activity.
Cognitive ability is also impaired in those with Huntington's disease, and behavioral changes can sometimes occur before movement problems become apparent. Schizophrenia has a large degree of overlap with Huntington's disease in terms of psychosis and behavioral changes.
Tocris offers the following scientific literature for Huntington's Disease Research to showcase our products. We invite you to request* or download your copy today!
*Please note that Tocris will only send literature to established scientific business / institute addresses.
Huntington's disease (HD) is a monogenic neurodegenerative disorder, which is characterized by the prevalent loss of GABAergic medium spiny neurons (MSN) in the striatum. This poster summarizes the MSN intracellular signaling pathways implicated in the pathology of HD, as well as highlighting the use of iPSCs for HD modeling.