Huntington's Disease

Huntington’s disease (HD) is an inherited neurodegenerative disease characterized by neuropsychiatric symptoms, movement disorders, and progressive cognitive impairment. It is caused by a mutation in the CAG repeat region of the HTT gene. The mutant huntingtin (mHTT) protein presents an expanded polyglutamine (polyQ) tract that confers the protein the tendency to misfold and form aggregates primarily in neurons. Misfolded mhtt interferes with normal cellular processes that result in neurodegeneration primarily affecting striatum, cerebral neocortex and sub-cortical white-matter but also other brain areas. The trigger event-driven is likely to occur many years before the first signs of neurodegeneration. Despite the single gene cause, a large number of downstream pathways are implicated in the disease pathogenesis including transcriptional dysregulation, decreased neurotrophic signaling, oxidative stress, unfolded protein response, protein degradation, glutamate-mediated excitotoxicity, mitochondrial fragmentation, reduction in ATP levels, and inflammation.
Sigma ligands reduce the size of Htt aggregates and protein misfolding, counteracting its effects by increasing cellular antioxidants, reducing the oxidative level, restraining inflammation, and promoting activity in macrophages, without changing mitochondrial Ca²⁺ concentration, also increasing the expression of neuroprotective factors, such as BDNF and DARPP32. Sigma ligands also inhibit the iron accumulation in neurons, by blocking the huntingtin interaction with the Amyloid precursor protein (APP), which also interferes with iron trafficking at the blood-brain barrier, contributing to synaptic defects and reduction in number, and decline in motor endurance.
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