No one really knows exactly how the expanded huntingtin protein causes neuronal cell death, or why it effects only the striatum, but there are several theories. These theories suggest that HD may effect cellular processes such as excitotoxic functions, metabolism, development, cytoskeletal structure, and vesicular transport.
One theory states that glutamine sticks to itself or other proteins in a zipper-like fashion. The tangled proteins then clump up and precipitate in the striatum. It used to be believed that precipitation of proteins in the striatum caused the symptoms of HD. This theory doesn't completely explain how HD is caused because the huntingtin protein is found in every cell. Now it is believed that this may be a side effect of the real damage.
A more promising study has shown that there is an increase in an enzyme called 3-hydroxyanthranilate oxygenase in the striatum. This enzyme produces quinolinate. Quinolinate in larger quantities somehow increases the likelihood of producing quinolinic acid, an endogenous excitotoxin. It is believed that the excitatory neurotransmitter glutamate's NMDA receptor may play a part in this excitotoxic process because quinolinic acid is an agonist at this receptor. The theory of how HD causes cell death isn't complete because the distribution of NMDA receptors doesn't correlate to where most of the cell damage occurs.
In order to determine what the protein huntingtin does, scientists from Duke University went fishing with the polyglutamine section of the huntingtin protein in human brain. They pulled out glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a key enzyme in glycolysis, the conversion of sugar glucose into energy. Both normal and expanded polyglutamine regions bind to GAPDH. GAPDH is the first enzyme correlated with the CAG repeat whose function is known. The brain relies almost exclusively on glycolysis for energy since there are no fat reserves in the brain. This finding has important implications. Perhaps neuronal cell death occurs because of a disruption of energy production through GAPDH. It has not been shown yet that the interference of glycolysis is responsible for the symptoms of HD. This theory is, however, supported by the finding that there is an increase in lactate concentrations in the basal ganglia and cerebral cortex in HD patients.
It is also possible that huntingtin plays a role in the development of the basal ganglia. Studies of MRI scans have shown that the basal ganglia is smaller than normal in people with an expanded polyglutamine region before the person begins to develop the symptoms of HD.
Another theory attempting to explain how cell death occurs and what the function of huntingtin protein is suggests that the huntingtin protein interacts with other proteins involved in the transport of vesicles along cytoskeletal structures. Two proteins, huntingtin's interactor protein (HIP1) and huntingtin's associated protein (HAP1), that interact with neurons cytoskeleton in unknown ways have been shown to bind to huntingtin protein. Interestingly, these two proteins are found only in the brain. This could explain why HD only affects the brain even though every cell in the body produces huntingtin's protein. Expansion of the polyglutamine region changes how huntingtin protein interacts with HIP1 and HAP1. The larger the region, the less huntingtin interacts with HIP1 and the more it interacts with HAP1. Much of how these proteins interact and what the interactions have to do with HD is yet to be discovered.
HD is more common in Northern European populations and less common in African and Asian populations compared to all populations. The huntingtin allele usually contains between 15 and 20 repeats. Northern Europeans frequently have a more repeats in this normal range, while Asians and Africans tend to be on the lower end of this range. Therefore, Northern Europeans may be predisposed to expansion on this allele.
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