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Basic Neurobiology of Huntington’s Disease Part 5
What happens in the brain following the onset of HD?
How does HD cause striatal and cortical nerve cells to die?
Not much is known for certain about how and why specific cells die within the basal ganglia of HD patients. This section will attempt to answer some of the questions scientists are currently asking themselves.
First of all, the huntingtin protein is present in all the cells of the body, not just nerve cells. Scientists currently do not know the exact details of the function of the normal huntingtin protein in the body, but they do know that huntingtin is necessary for development and is active throughout the body. However, HD does not kill all the cells in the body; rather, it selectively kills nerve cells. The effects of HD seem to suggest that the huntingtin protein regularly interacts with proteins found only in the brain, and that the altered form of the huntingtin protein disrupts this interaction, leading to nerve cell death.
Various experiments have revealed that the huntingtin protein interacts with two proteins: huntingtin’s interactor protein (HIP-1) and huntingtin’s associated protein (HAP-1). These two proteins are present only in the brain, and this finding could explain why HD only affects the brain even though the huntingtin protein is present throughout the body. The number of C-A-G repeats in the huntington gene determines how the huntingtin protein interacts with HIP-1 and HAP-1. As repeat numbers increase, huntingtin binds less to HIP-1 and more to HAP-1. Much information about how these proteins interact and what these interactions have to do with HD has yet to be discovered. The figure below shows the proposed interaction of the altered huntingtin protein and HAP-1.
Other questions scientists are attempting to answer include: Why is the striatum predisposed to damage? Why are certain populations of striatal neurons selectively targeted during the start of HD? A couple of theories have been presented, but scientists are still working on determining the exact events involved in the progression of cell deaths caused by HD.
One theory proposes that neurons die in HD because of an over-accumulation of normal excitatory chemicals involved in nerve impulses. Excitatory chemicals are important, and they are normally present in the brain. However, if they are released in excessive amounts or if brain cells are weak, these excitatory chemicals can cause cell damage and become chemicals known as “excitotoxins.” One of the neurotransmitters released by the basal ganglia is called glutamate, which acts as an excitatory neurotransmitter in the brain. Studies show that when glutamate is injected into the basal ganglion region of brains of living rats, the rats exhibit symptoms of HD because glutamate apparently acts as an excitotoxin when there is too much of it. Scientists speculate that striatal neurons may be receiving too much glutamate from other nerve cells that release glutamate as a neurotransmitter. Other experiments have also shown that nerve cells that receive too much glutamate will die.
This first theory had to be modified when high levels of glutamate were not found in the brains of all HD patients. The modification has to do with mitochondria – a type of organelle (mentioned near the beginning of this section) that produces energy in animal cells. The mitochondria of striatal cells may be damaged with the onset of HD, leading to their increased susceptibility to even normal levels of glutamate. Scientists have since then done away with the idea that too much glutamate is being released by other cells. Rather, scientists currently believe that the damaged mitochondria of people with HD make striatal cells unable to produce as much energy as they need, which then makes the cells more susceptible to normal levels of glutamate.
Another theory to explain the death of nerve cells postulates that the cells actually kill themselves in response to chemical changes caused by HD. The theory proposes that HD triggers the early death of neurons by accelerating a normal process called apoptosis, or “programmed cell death.” Scientists are studying whether the presence of the altered huntingtin protein—a molecule produced within the nerve cells themselves—causes nerve cells to die prematurely. (See Basics of Huntington's Disease.) Researchers have inserted the human HD gene into mice in order to see what happens to the nerve cells of these modified mice. They found that nerve cells of these mice contained clumps of protein material in their nuclei called neuronal inclusions (NI). They then looked at nerve cells of people with HD and saw that such clumps were also present in their nerve cells. Further studies have revealed that these clumps actually contain only a part of the altered huntingtin protein, suggesting that the altered huntingtin is, at some point, cut into fragments, some of which end up as clumps in the nucleus.
But there is a further complication: all living cells continually break down and destroy proteins as part of their normal activity, either because the proteins are misfolded, are no longer needed, or are aberrant in some way. What’s puzzling is that the altered form of huntingtin is not completely broken down by the cell. Why not, when so many other aberrant proteins are degraded all the time in animal cells? Scientists are currently looking at reasons for this anomaly. Studies are also being carried out to determine whether the NIs actually cause nerve cell death or are only by-products of some other problem.
To sum up, the neurobiological effects of HD appear to be the result of a number of different changes that ultimately go out of control. Neurobiologist Anne Young has proposed a model for how HD disrupts cell function. According to Dr. Young, the problem starts when the extended C-A-G repeats of the huntingtin gene code for an altered form of the huntingtin protein. The altered huntingtin then interacts with various proteins in nerve cells and causes the nerve cells of people with HD to become very sensitive to glutamate. This increased sensitivity leads to the activation of other proteins called caspases that cleave huntingtin to smaller fragments. The fragments then slip into the nerve cell’s nucleus and interfere with the normal production of other proteins. This interference causes cellular stress that could then lead to more huntingtin being broken up into fragments, initiating a cycle that eventually leads to the death of the nerve cell.
Researchers believe that increased understanding of how HD progresses will further the development of new pharmaceutical drugs and other therapies that will one day serve as treatments for HD. In fact, one implication of the neurobiology reviewed here is that different drugs might well be used someday to target different stages of HD progression. For example, drugs to lessen the sensitivity of nerve cells to glutamate could be administered at the start of HD. Later on, as the disease progresses, drugs that prevent the huntingtin protein from being cleaved could be given. Hopefully, with continued neurobiological research, treatments such as these will become a reality and HD will cease to be a devastating disease.
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-E. Tan, 8-22-01
For further reading:
Cha, Jang-Ho and Young, Anne B. Huntington’s Disease.Online. This page contains lots of information about the HD, including its history, neurobiology, and genetic aspects.
Hereditary Disease Foundation. Fast Paths to a Cure. Online. This is a pdf file that contains notes of a scientific workshop held January 8-9, 2000. Read it for more information on recent findings, upcoming studies, and challenges in the scientific world as researchers attempt to find a cure for HD.
Pi, Ruolan. Huntington’s Disease. Online. More information on the neurobiology of HD. This page focuses on the excitotoxicity theory and contains highly technical information about it.
Quarell, Oliver. Huntington’s Disease: The Facts (Oxford Medical Publications). Oxford University Press, 1999. This book is an absolutely great resource for anyone interested in HD. It contains lots of information about the neurobiology and genetics of HD in an easy-to-understand format. It’s available at the following web sites:
The Huntington’s Disease Society of America: www.hdsa.org
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