Neurodegenerative Disease

Huntington’s Disease

Huntington’s Disease Lab SampleHuntington’s Disease (HD) is an autosomal dominant genetic disorder characterized by a CAG trinucleotide repeat expansion that results in a dominant polyglutamine-expanded region in mutant huntingtin proteins (mhtt). Critical polyQ tail lengths in the upper 30s have been linked to a novel polyQ conformation that is pathogenic, where patients experience neuronal loss within the striatum and cerebral cortex resulting in mood swings, depression, impaired judgment, involuntary movements, slurred speech and ultimately death. Elevated copper and iron concentrations have also been observed in the striata of HD patients and affected HD transgenic mice, and it has even been suggested that these redox metals may interact directly with and oxidize the polyQ-containing N-terminal fragment. Although the nature of this interaction and subsequent reduction reaction remains unclear, researchers have conclusively shown that accumulation of redox metals is a significant contributing factor to oxidative stress in Huntington’s disease and more broadly to neurodegenerative disease progression. Detailed, metal selective spectroscopic interrogation of mhtt will provide valuable insight into the electronic structure, geometry, ligation, and redox properties of the metal environment, and may help elucidate the mechanism by which copper contributes to disease progression. Further studies will define possible avenues to enhance the selectivity of commonly used chelation therapeutics presently administered to reduce the severity of HD symptoms.