Healthcare reform has been a hot topic in the United States in recent years, and many important changes are continually being made. In this article, we will take a look at some alterations that are particularly relevant to HD patients and their families. The first half of the article discusses the Genetic Information Nondiscrimination Act (GINA), and how it impacts insurance and employment for individuals who are at-risk for genetic conditions like HD, as well as those who are considering a genetic test. Next, this article covers the new Affordable Care Act, and changes to insurance policies for patients with pre-existing conditions, such as HD.
GINA is meant to prohibit health insurers and employers from discriminating against anyone based on genetic information. This means that no one can be denied insurance or charged a higher premium based on genetic information, and that health insurance companies cannot request genetic information from any person or their family members. In addition, employers cannot make decisions about hiring, firing, or promotion based on genetic information.
Any genetic tests of an individual, including those done in a research study. A genetic test is formally defined as “an analysis of human DNA, RNA, chromosomes, proteins, or metabolites that detects genotypes, mutations, or chromosomal changes.”
Results of a genetic test or record of participation in services such as genetic testing, genetic research, and genetic counseling for an individual’s family members, up to 4th degree relatives
GINA does not apply to life insurance, disability insurance, long-term care insurance, and employers with fewer than 15 employees.
It is also important to note that GINA is not retroactive, meaning that any decisions made before the law came into effect cannot be challenged. However, any employer or insurer who holds genetic information can no longer use it, even if the information was obtained before GINA existed.
Once someone exhibits symptoms of a genetic disease or disorder, that individual is not covered by GINA. In this case, any insurance or employment decisions made based on the existing condition are legal. For patients at this stage of disease, the Affordable Care Act of 2010 may be relevant.
Signed in March of 2010, the Affordable Care Act introduces a wide variety of changes to health insurance policies and costs in the United States. Its various components are being implemented independently, so pay attention to when each change becomes law!
What if I have HD and don’t have insurance right now?^
Under the Affordable Care Act, adults with existing disabilities and mental or physical illnesses cannot be denied health insurance coverage as of January 1, 2014. The same rule has been in place for children since September 23, 2010.
If you are an HD patient, one current option for coverage is the Pre-Existing Condition Insurance Plan (PCIP) in your state. Some states are choosing to operate their own PCIPs, while others are offering federally-run plans.
All legal U.S. residents who have been without insurance for at least six months may apply for PCIP coverage. This also applies to those who have been denied insurance or charged an unaffordable premium in the past due to their condition. Eligibility is not based on income. PCIP covers primary and specialty care, hospital care, and prescription drugs, including any services needed to treat or manage a pre-existing condition. Note, however, that a positive genetic test for HD cannot be considered a pre-existing condition, so individuals with a positive gene test can and should apply for regular insurance programs instead of PCIP.
Currently, because PCIP premium amounts vary from state to state, some patients may need to apply for Medicaid or other assistance programs if PCIP costs are too high. In these cases, all terms and conditions for Medicaid eligibility must be met, regardless of any pre-existing conditions. Gaining better coverage for low-income or unemployed individuals is an ongoing effort, but there has not been significant progress on this front.
If you have had health insurance coverage since September 23, 2010, your insurer cannot unfairly cancel coverage, deny services, or raise premiums, even if your condition worsens and demands expensive treatments or medications. This applies even if you accidentally forgot to mention a symptom experienced or treatment received when submitting your insurance application. Note, however, that intentional omissions, untrue information, and late payments can still be used as reasons to cancel coverage or refuse services.
Lifetime dollar amount limits on essential services have also been illegal since September 23, 2010, and annual limits will be banned for many services after January 1, 2014. If financial hardship or another extenuating circumstance causes you to lose coverage, insurers must provide a 30-day warning before terminating your policy. You will be eligible to apply for PCIP 6 months after the termination.
A new Healthcare Exchange program is currently in the works, and may provide better coverage or lower premium options for patients with pre-existing conditions, such as HD. Many changes have been discussed and considered in Congress over the past few years, so staying informed about the latest developments in healthcare reform is necessary and helpful.
Even when a person is at risk for developing HD there are many things he or she can do about it. Yes, everyone with the HD allele will eventually display symptoms of HD. However, the expression of these symptoms is subject to great variability. For example, studies of the HD population in Venezuela revealed that there is great variability in the age of onset (the age at which symptoms first appear) of HD. While the number of repeats of the CAG codon is the most important factor in determining age of onset, it is not the only factor. There may be a big difference in the age at which two individuals with the exact same repeat length-and even genetically identical twins-begin expressing symptoms of HD. Researchers found that, after controlling for repeat length, about 60% of the variance in age of onset is environmental (“variance” is a statistical measure of variability). This important finding means that genes do not completely determine the expression of HD: the environment plays an important role. The implication is that everyday practices regarding diet, exercise, and stress management can greatly influence the onset and progression of HD. While these practices are by no means “cures” or even treatments for HD, they do promote health. Also, it is important to realize that while a correlation may exist between such practices and good health, and even improvement in HD symptoms, that correlation does not mean that the practices are themselves causing the good results. Other factors may be involved. In any event, it is important to consult your medical doctor before making any drastic changes in your lifestyle.
General health promotion strategies address the mental, physical, spiritual, and social connections of who we are and how we live. Through both action and inaction people make choices about their health on a daily basis. Each of us has general health strategies that we are implementing all the time. The purpose of this chapter is to provide information about life practices that promote general health, and to explore how these life practices may affect the way that individuals respond to HD. Despite the fact that people with the HD allele will eventually show symptoms, the expression of these symptoms can be greatly influenced by the lifestyle choices that those individuals make.
Welcome to the “Drugs and Supplements” section of the HOPES website! Articles within this section will frequently use the terms “treatment” and “cure.” Please note, though, that the word “treatment” must not be confused with the word “cure,” for there is currently no medical cure for Huntington’s Disease (HD). However, while no existing drugs can actually stop or reverse the neurologicaldegeneration that HD causes, most if not all HD patients can benefit from the management of certain symptoms associated with HD, such as chorea, psychosis, and depression. There are well-tested drugs that have been developed to treat these symptoms, and such therapies may help ease the frustration, embarrassment, and emotional pain that often accompanies HD. In general, these drugs can greatly enhance the quality of life for HD patients and their families. Information on such symptoms and their treatments can be found by clicking here.
The “Drugs and Supplements” section of the website focuses on identifying and explaining the current research on various potential treatments aimed at stopping the progression of HD. We must make it clear that HOPES does not advocate the use of any of the therapies described without the consent or approval of a doctor, and cannot provide medical advice of any kind. However, we do hope that patients with HD, their friends, and their families will ask doctors and HD specialists about both the possibilities presented here and any new developments in this active area of investigation. In the past decade, intensive research efforts have given scientists a much better understanding of how HD damages the brain. With this improved insight, researchers throughout the world are actively investigating and testing the efficacy of drugs that target one or more of these mechanisms of pathology. Their hope is that interfering with HD’s damaging pathways can help delay, stop, or reverse the course of the disease.
This section is organized by disease mechanism. A potential contributor to HD’s damaging effects is introduced, followed by the drugs and supplements currently being studied to counter a given mechanism. For your convenience, a simple alphabetical list of these drugs can also be found by clicking here. Each drug profile also has a short drug summary that avoids potentially difficult and confusing details.
The therapies introduced in this section are at various stages of investigation. Some have been at the heart of well-controlled experiments on mouse or fruit fly models of Huntington’s disease, and others have shown some efficacy in treating disorders with disease mechanisms similar to HD’s such as Alzheimer’s Disease or Spinobulbar Muscular Atrophy (SBMA). There are also many that are being studied simply for their theoretical potential in alleviating HD’s degenerative damage. Because many of the treatments profiled here have not yet passed or even begun clinical trials, and many affect broad biological systems, HOPES must again stress that unsupervised testing could be potentially hazardous. None of these therapies should be tried without exclusive consultation with an HD specialist.
Most scientists believe that a combination of treatments, rather than a single treatment, will be needed in order to cure HD. The different therapies could work together to combat different aspects of HD’s damage mechanisms, and hopefully halt or reverse its progression. Similar therapeutic approaches are currently being used with varying levels of success to controlcancer and AIDS.
While this section focuses on the potential drug and supplement candidates for treating HD, various potential treatment options beyond drugs also exist. Recent advances in gene therapy, stem cell research, and neurosurgery are some of the potential long-term solutions being studied. Some of these therapies are becoming available for clinical trials, while others still require further development. (For more information on Huntington’s Disease research in America and in your region, click here.)
Serotonin (also known as 5-HT) is a neurotransmitter used to communicate important information between nerve cells. Serotonin is sometimes referred to as the “feel good” neurotransmitter owing to its association with elevated mood levels. It also has many other functions in the central nervous system including roles in sleep, depression, memory, pain, and aggression. Recent studies on mice indicate that serotonin signaling is significantly reduced in mice models of HD compared to mice without HD. Having less serotonin and the products made from serotonin may greatly impact on the progression of HD. Because the connection between HD and serotonin signaling is a fairly new development, much more investigation needs to be done before there are clear answers. Decreased serotonin may be a contributor to the development of HD or it may simply be a result of another disease mechanism. Regardless of the cause for reduced serotonin, diminished signaling in the mouse model of HD may explain some of the common behavioral symptoms associated with HD in people. (For more information about the behavioral symptoms associated with HD, click here.)
Decreased serotonin is associated with several diseases, most notably depression. Consequently, a number of drugs are already available to help bring serotonin back to normal levels in the body. The main class of drugs for this purpose is called selective serotonin reuptake inhibitors (SSRIs). Recent research has shown that, in addition to alleviating symptoms associated with HD such as depression, SSRIs may also help delay the onset of HD and prevent the degeneration of nerve cells.
Researchers have found elevated serotonin in the brains of people with HD after death, but serotonin levels in a mouse model of HD actually have decreased levels in all different age groups. However, this discrepancy does not necessarily mean that the mouse data is wrong. First of all, it is difficult to interpret human HD samples taken after death due to the large amount of nerve cell loss that occurred in life. Most of what is known about serotonin and HD in living brains comes from mouse studies because it is easier and more ethical to experiment on mice that are made to look like they have HD than it is to study humans with HD. It is important to keep this fact in mind when discussing the findings from these studies because the results from experiments on mouse models do not always translate perfectly to people with HD. Mouse studies are an imperfect but important tool in learning about HD.
Another group of researchers tested the hypothesis that the serotonin system starts malfunctioning before it is observable with decreased serotonin. Since serotonin levels could not be used as a marker in this experiment, they tested the rate-limiting enzyme in the synthesis of serotonin, tryptophan hydroxylase (TPH). A rate-limiting enzyme is the slowest step in the creation of a molecule, and often the most important, because it requires additional energy and is highly regulated. The rate-limiting enzyme can have the biggest effect on the final product, so if something is wrong with it, the effect of this malfunction will translate down the chain to the end product. You can think of synthesis as a row of dominoes, with the goal to knock down the final domino. If one of the dominoes is missing or too small to reach the next one, the rest of the dominoes in the chain will not fall down and you will not achieve your goal. As a rate-limiting enzyme, TPH is essential to the overall production of serotonin. An alteration of TPH can therefore lead to decreased levels of serotonin in the brain overall.
Researchers have tested both the levels of TPH and its enzymatic activity. Despite normal levels of TPH, they found the activity of this enzyme was significantly diminished. This finding means that while the enzyme was present, it was not functioning properly. TPH activity was 62% less than normal before symptoms were present at 4 weeks and 86% less than normal in symptomatic 12 week old mice. These results indicate that TPH is severely damaged and account for the decreased levels of its product, serotonin.
We must now ask, “Why is TPH activity decreased?” The obvious answer might be that mutant huntingtinprotein prevents TPH from doing its job; however, this appears unlikely. The researchers tested this hypothesis and found that the expanded polyglutamine section of the mutant huntingtinprotein does not interact with TPH. Another possibility comes from the fact that TPH is very sensitive to free radical damage by reactive oxygen species. (For more information on free radical damage, click here.) It is already known that free radical damage plays a role in the progression of HD, so it is very possible that it contributes to decreased serotonin by interfering with TPH. More evidence about the role of free radicals comes from the decreased activity of TPH. Since TPH uses tryptophan to create certain products, when TPH doesn’t work, this pathway is disrupted. This disruption results in increased levels of 3-hydroxykynurenin (3HK), which makes free radicals. These free radicals can then go on to further damage TPH and many other molecules in the brain.
Now that researchers have an idea of the problem, they can begin to investigate ways to fix it. First, it must be determined whether TPH activity is also decreased in human brains, since so far it has only been tested in mice. If it is also decreased in humans, that could explain why depression is apparent before any of the motor symptoms of HD. If the current hypotheses from the mouse studies are correct, symptoms may be prevented or at least delayed by treating people at risk for HD with early antioxidants and SSRIs to keep TPH activity and serotonin levels normal. It has already been shown that one type of SSRI helped to increase TPH activity in rats.
Aside from impaired energy production, damage to the mitochondria leads also to increased production of toxic molecules called free radicals. Compounds called antioxidants act as free radical scavengers by initiating reactions that make free radicals non-toxic to cells. Evidence indicates that damage by free radicals is a contributing factor to the pathology of HD. Consequently, compounds with antioxidant properties are being studied to see if they can serve as possible treatments for HD.
Free Radicals and Antioxidants
Free radicals are atoms or molecules that are highly reactive with other cellular structures because they contain unpaired electrons. Free radicals are natural by-products of ongoing biochemical reactions in the body, including ordinary metabolic processes and immune system responses. Free radical-generating substances can be found in the food we eat, the drugs and medicines we take, the air we breathe, and the water we drink. These substances include fried foods, alcohol, tobacco smoke, pesticides, air pollutants, and many more. Free radicals can cause damage to parts of cells such as proteins, DNA, and cell membranes by stealing their electrons through a process called oxidation. (This is why free radical damage is also called “oxidative damage.”) When free radicals oxidize important components of the cell, those components lose their ability to function normally, and the accumulation of such damage may cause the cell to die. Numerous studies indicate that increased production of free radicals causes or accelerates nerve cell injury and leads to disease.
Antioxidants , also known as “free radical scavengers,” are compounds that either reduce the formation of free radicals or react with and neutralize them. Antioxidants often work by donating an electron to the free radical before it can oxidize other cell components. Once the electrons of the free radical are paired, the free radical is stabilized and becomes non-toxic to cells. Therapy aimed at increasing the availability of antioxidants in cells may be effective in preventing or slowing the course of neurological diseases like HD.
Huntington’s disease (often abbreviated “HD”) was first described in medical literature in 1872 by Dr. George Huntington, a physician from Long Island, New York. The disease affects men and women alike, occurring at a rate of about one in every 10,000 in most Western countries. People with HD need dedicated care and support from their loved ones, which makes the number of lives touched by the disease even greater.
The age of onset of Huntington’s disease is normally between 30 and 50 years old, although there is also a form of HD that affects children and teenagers. People with HD may express a wide variety of symptoms, which physicians typically group into three categories: movement, cognitive, and psychiatricsymptoms.
Some of the movement symptoms of HD include muscle spasms, tics, rigidity, falling down, difficulty physically producing speech, and, in the later stages of the disease, difficulty swallowing (which can lead to significant weight loss). Uncontrollable movements such as writhing and twisting are also quite common symptoms of HD. Physicians sometimes refer to these uncontrollable movements as “chorea”.
The most significant cognitive symptoms of HD are the altered organization and generally slowed processing of information in the brain. These symptoms can lead to difficulty learning new things, difficulty planning and prioritizing, impairment of one’s perception of space (where one is in relation to tables, walls, etc.), and difficulty “multitasking” (paying attention to several things at once). Individuals frequently adhere to common routines because these routines are the easiest for them to accomplish. Finally, because they have trouble organizing incoming and outgoing words in their brains, many people with HD experience difficulty communicating with others.
Depression is the most common of the psychiatric symptoms of HD. Other symptoms include personality changes, apathy, anxiety, irritability, obsession with certain activities (such as hand washing), delirium, and mania. Denial of having HD is also a common symptom of the disease.
Sadly, somewhere between 10 and 25 years after symptoms first appear, HD usually takes such a toll on individuals that they die of pneumonia, heart failure, or other complications.
HD causes deterioration of the nerve cells in the brain, prompting significant changes in one’s ability to think, feel, and move. The cause of these symptoms remained a mystery for quite some time until doctors noticed that the disease “ran in families” and suspected its hereditary basis. The inheritance of HD (like other hereditary traits) is now known to depend upon a “chemical code” of information contained in a substance called deoxyribonucleic acid, or DNA, which exists within living cells. Understanding a bit about this chemical code helps to give better insight into the causes of HD and into treatments that may one day lead to its cure.
The chemical code of DNA is a lot like the English language: both use specific letters in a specific order to communicate specific things. But while the English language has 26 letters, the DNA code only has four–A, C, G, and T (which stand for chemical subunits of DNA). Also, while English words can consist of either a few or many letters, DNA “words” are always three letters long. In the study of genetics, these three-letter “words” are called codons. Aptly named, codons code for the future building that goes on in the nerve cell. They are a bit like blueprints. Consider this example: when a passage contains the letters C-A-T in English, this paints a picture of our favorite lazy pet. In much the same manner, when the code of DNA contains the letters G-G-C, this tells the cell to build with proline, an amino acid. For more about DNA, click here.
If codons are like blueprints, then we can think of the amino acids that result from them as unique building blocks. When these blocks are put together chemically, they create a structure known as a protein. Like buildings in modern society, proteins are where the work of the nerve cell gets done. Proteins have many different jobs: they help the cell maintain its structure, produce energy, and communicate with other cells. If it were not for the body’s millions of proteins, life as we know it could not occur.
The specific actions of a protein are determined by its unique 3-dimensional shape. This shape controls how the protein can “fit in” and interact with other parts of the cell. The shape is determined by the type of amino acids that compose the protein, as well as by the specific order they are in. Thus, as with any well-engineered building, a successfully functioning protein starts with the “blueprints” (codons).
All human cells contain a protein called huntingtin. (Please note that although “Huntington’s disease” is spelled with an “o”, the correct spelling of the protein involved is “huntingtin” with an “i.”) Although scientists have yet to determine huntingtin’s exact function, it seems to play a critical role in the events that help nerve cells function effectively. Like many other proteins, huntingtin contains within it the amino acidglutamine. In people with HD, however, there is an excess number of glutamines in a particular segment of the protein. These extra glutamines come from having too many copies of the corresponding codon (the one that codes for glutamine) in the chemical code of DNA. That codon has the letters C-A-G. In a very real sense, HD results from having too many copies of C-A-G in the DNA that codes for huntingtin protein. That is why HD is often referred to as a trinucleotide repeat disorder (“trinucleotide” being a fancy word for codon).
Exactly how many copies of C-A-G are too many? A great deal of research has been done in this area and there are many different opinions throughout the scientific literature in answer to this question. Rough estimates are as follows: People with 10 to about 35 copies of C-A-G have a normally functioning form of the huntingtin protein. Those with 40 or more have the altered huntingtin and will eventually develop symptoms of HD. For people who have 36 to 39 copies of C-A-G, the outcome is less clear. Some will develop the symptoms of Huntington’s disease and some will not. To learn more about how HD is passed on through generations, click here:
To summarize the above, Huntington’s disease is caused by too many copies of the codon C-A-G in human DNA, which puts too many copies of glutamine in the huntingtin protein. But exactly how is the altered huntingtin damaging? Unfortunately, despite valiant efforts by researchers, a definite answer to this question has yet to be found. Since the shape of the protein determines its interactions with other parts of the cell (as we learned earlier), much of the research to this point has sought to understand exactly how a shape alteration affects huntingtin’s interactions with the other components of the cell. One study suggests that the overabundance of glutamines in huntingtin causes rigid groupings of proteins. Since the components of the nerve cell are accustomed to a more flexible environment, they cannot work under the increased rigidity. The end result is basically early cell death of the nerve cell through a process called apoptosis. Another recent study suggests that the altered (and larger-than-normal) huntingtin “kidnaps” smaller proteins in the nerve cell, keeping them from doing their jobs. In this way, the altered huntingtin could indirectly damage the nerve cell. (For more information about alteredhuntingtin protein, click here.)
While scientists continue to work out the fine details of HD, the basic mechanism is clear. Continuing with our construction analogy, what happens when huntingtin is made in the altered form is that the “building” (the protein) does not have the specific size and shape that it was meant to have, and thus cannot function correctly in the “metropolis” that is the nerve cell. When it cannot function correctly, it hinders the action of other proteins that depend on it. The end result is a snowball effect, where the problems are continually compounded and the nerve cell becomes more and more damaged. Ultimately, after enough damage occurs, the nerve cell dies. When many other nerve cells follow suit, the problems of thinking, feeling, and moving that are associated with HD can result. For more information on nerve cells and how their deaths relate to the symptoms of HD, click here:
To leave feedback about this section of the HOPES website, please click here. Make sure to specify which article you’re referring to.
Australia’s “Cooperative Research Centre for Discovery of Genes for Common Human Diseases” (Gene CRC) Web site has some fabulous tutorials at various levels of understanding.
Cummings, C. J and Zoghbi, H.Y. “Trinucleotide Repeats: Mechanisms and Pathophysiology.” Annu. Rev. Genomics Hum. Genet. 2000. 1:281-328. A fairly technical chapter explaining the symptoms of HD, as well as a breakdown of the number of CAG repeats in people with and without the disease. Also discussed are theories regarding the function of the alteredhuntingtin protein.
Falush D, et al. “Measurement of mutational flow implies both a high new-mutation rate for Huntington disease and substantial under ascertainment of late-onset cases.” Am J Hum Genet 68 (2) 2001 Feb: 373-385. A technical analysis of the number of CAG repeats that is believed to determine whether one will develop the symptoms of HD.
“Huntington’s Disease”. Online Mendelian Inheritance in Man. A compilation of abstracts from a multitude of different studies on HD. From case studies regarding inheritance to new methods of diagnosing HD, this is an excellent site for all the various types of HD research going on today.
The altered huntingtin protein responsible for HD has been shown to contain many more molecules of the amino acid glutamine than regular huntingtin. This abundance of glutamine is due to repetitive copies of the CAG codon in the Huntington gene. The extended glutamine tracts of these proteins have affinity for one another, and tend to “stick together,” leading to the formation of “clumps” or aggregations of the protein in the cell’s nucleus. These protein aggregations are often referred to as neuronal inclusions (NIs).
It is not absolutely clear whether NIs are the cause or the result of HD, or whether they might even be a defense mechanism against it. Scientists are not certain whether the NIs themselves are toxic, or whether the intermediates or building blocks in the aggregation process are the toxic agents. These questions aside, there is mounting evidence supporting NIs as a primary mediator of cellular toxicity in Huntington’s disease.
There are two major lines of thought regarding the toxic mechanisms of polyglutamine protein aggregation. One is that other normal molecules with glutamine tracts get “trapped” within the NIs, and are therefore prevented from performing their normal functions. Another is that the NIs “clog” the Ubiquitin-Proteasome System (UPS), a kind of disposal system that is essential for normal cell function. For more information on the role of protein aggregation in the progression of HD, click here.
Scientists have shown that reducing the amount of protein aggregation in the cell may be beneficial for patients with HD. The drugs listed under the “Protein aggregation” navigation menu potentially reduce the amount of NIs in the cell, and are therefore being researched as possible treatments for HD.
Compounds that have the ability to regulate the transcription of specific sets of genes are being proposed as possible candidates for treating HD. Some of these compounds may be able to regulate genes to produce proteins that could delay various HD symptoms. For example, some of the drugs could induce the transcription of genes responsible for the production of proteins with anti-inflammatory effects. Because inflammation has been found to play a role in the destructive effects associated with HD, the production of proteins with anti-inflammatory effects could be beneficial for people with HD. The drugs listed under the “changes in gene transcription” subcategory act to induce gene transcription and increase production of proteins beneficial for people with HD, and are therefore being looked into as possible HD treatments.
The mutant huntingtin protein has been found to disrupt cellular metabolism, the process by which cells make energy. It interacts with key proteins needed to produce energy and causes damage to mitochondria, the ‘energy factory’ of the cell. Mitochondria produce energy in the form of molecules known as ATP (for “adenosine triphosphate”). The amount of ATP available to cells is lower in Huntington’s Disease (HD), which makes cells more susceptible to damage by toxic compounds. Scientists are looking into drugs and supplements that increase the amount of energy available in cells, as they might be possible candidates for treating HD. This article explains how huntingtin affects cellular metabolism, which is important for understanding how these drugs may improve energy production in the cell.
The Basics of Energy Metabolism
Energy metabolism is a process by which the food we eat is broken down by various enzymes in order to produce a molecule called ATP, the energy source of the cell. The pathway by which ATP is produced depends on the availability of oxygen in cells. If there is a sufficient amount of oxygen, aerobic respiration takes place in the mitochondria and large amounts of ATP are produced. If there is not enough oxygen in cells, anaerobic respiration is instead performed, which produces a smaller amount of ATP. Thus, aerobic respiration is a more efficient process because it produces more energy from the food we eat.
Glycolysis is a series of reactions that begins the process of metabolism in all cells. It takes place in the cytosol (sometimes also called “cytoplasm”), which is the fluid portion of the cell.
The important molecular product of glycolysis is called pyruvate, which can undergo either aerobic or anaerobic respiration. If sufficient oxygen is present, pyruvate gets transported to the mitochondria where it undergoes aerobic respiration. Each step of this process helps convert the food we eat from one molecule to another until ATP is produced as the end product.
HD and Cellular Metabolism
Exactly how mutant huntingtin interferes with energy production is unknown, but studies have revealed that it interacts with a variety of key proteins involved in energy metabolism. For example, the altered huntingtin protein interacts with a molecule known as GAPDH (which stands for glyceraldehyde-3-phosphate dehydrogenase), a key enzyme in glycolysis, the early part of metabolism described above. Huntingtin’s interaction with GAPDH partially prevents it from working properly. Research suggests that GAPDH interacts preferentially with small subunits of huntingtin protein rather than the full length protein. But this is precisely what the altered huntingtin becomes in people with HD: the altered huntingtin protein is readily cleaved into small pieces by proteins called caspases. (Click here to read more about caspases, or here for a figure depicting the effects of caspases in a nerve cell.) As HD progresses, cleavage by caspases is enhanced, generating more protein fragments. These fragments then interact with GAPDH and inhibit its activity, which leads to lower amounts of ATP available in cells and eventually causes cell death.
The mutant huntingtin protein is believed to have a greater impact on cellular metabolism when it has a longer glutamine tail, which happens when an individual’s copy of the HD allele has a longer segment of CAG repeats. Cells engineered to express huntingtin with particularly long polyglutamine tails were significantly worse at making ATP than cells expressing huntingtin with medium-length polyglutamine tails.
Damage to Mitochondria
Aside from interfering with one of the enzymes involved in glycolysis, mutant huntingtin also interferes with oxidative phosphorylation, the final step in aerobic respiration. Specifically, mutant huntingtin makes the electron transport chain less efficient. The electron transport chain is a series of protein complexes that are found in the membrane of mitochondria, and is a vital component of oxidative phosphorylation. The protein complexes are named Complex I, II, III, and IV. As electrons are transported from one complex to another, protons (H+) are pumped out into the space between the inner and outer membrane of the mitochondria. As protons are pumped into the space between the two membranes, a proton gradient forms – more protons are present in the space between the two membranes. The proton gradient is essential in ATP production. The protons that accumulate between the two membranes are then transported through a molecule called ATP synthase. ATP synthase then produces ATP molecules that the cell uses as its source of energy.
Most studies report that HD cells exhibit reduced activity in complex II and III. A few studies have also reported decreased activity in complex I as well. Scientists are still not certain how the huntingtin protein interacts with these protein complexes. They currently speculate that that the altered huntingtin protein may indirectly interfere with these complexes by interacting with other molecules involved in the electron transport chain. As the altered huntingtin protein disrupts this step of metabolism, the cell experiences more energy deficits, with some experiments suggesting that neurons in the striatum, a region of the brain heavily affected in HD, make 30% less ATP than non-HD neurons. This makes those brain cells more susceptible to damage by toxic substances such as glutamate.
In summary, because of damage to mitochondria in neurons of people with HD, aerobic respiration is less efficient and therefore produces less energy. Compounds that target different parts of the pathways of aerobic respiration are currently being studied to determine if they increase the energy supply available to cells and may therefore be potential drugs for HD.
As mentioned earlier, anaerobic respiration occurs when there is not enough oxygen available to cells. Anaerobic energy producing pathways are called fermentation. Organisms that do not need oxygen in order to grow and survive rely on fermentation as their main source of energy. Examples of such organisms include bacteria. During exercise, our skeletal muscles also rely on fermentation for energy during the few moments when insufficient amounts of oxygen are available. Fermentation produces lower amounts of energy and releases various by-products. In the muscle, the by- products of fermentation include molecules called lactate (also known as lactic acid). The accumulation of lactic acid is what makes our muscles hurt when we exercise. A summary of the steps involved in anaerobic respiration is shown below.
If you remember, the altered huntingtin protein has been found to partially inhibit the activity of the GAPDH enzyme, resulting in impairments in glycolysis. Given that fermentation requires the products of glycolysis in order to occur, how then can fermentation still occur in HD cells? It turns out that partial inhibition of GAPDH still allows some fermentation to occur, although complete inhibition would block glycolysis, and consequently, fermentation.
The altered huntingtin protein has been found to interfere with an enzyme involved in glycolysis and the electron transport chain. As a consequence, more fermentation occurs relative to aerobic respiration. Studies have reported that people with HD have increased brain lactate levels, indicating damage to mitochondria and impaired energy metabolism. Lactate levels are often used in studies to measure the efficiency of a drug or supplement. Lower lactate levels after treatment is seen as an indication of improved metabolism in cells.
The Big Picture
So what do defects in energy metabolism mean for people with HD? Brain scans reveal that people with HD metabolize glucose more slowly in certain parts of the brain. One of those regions, the basal ganglia, is responsible for controlling movements. Patients with particularly impaired metabolism in the basal ganglia have worse motor symptoms and lower functional capacity. Moreover, some scientists think that defective energy metabolism is partly responsible for the weight loss that many people with HD experience, as described in more detail here.
The drugs outlined in this “Abnormalities in Energy Metabolism” section are meant to boost energy, and hopefully reverse some of the effects described in this article.
Autophagy is a process by which a cell breaks down and recycles its own components. In normally functioning animal cells, autophagy occurs at a very low level. Autophagy pathways are activated when a cell is running low on nutrients. The cell breaks down already existing proteins and other cell components into their basic building block components so that they can be reused to maintain essential cellular functions. There is also evidence to suggest that autophagy can be used by the cell to break down misfolded proteins.
The induction of autophagy in Huntington disease (HD) cells results in the accelerated breakdown of huntingtin aggregates and has been shown to have neuroprotective effects. It is currently unknown whether huntingtin aggregates are the cause or result of HD, but nerve cells that build up huntingtin aggregates often die. To read more about huntingtin protein aggregation and its role in HD, click here.
The Process of Autophagy
The part (or parts) of the cell that is to be degraded is first engulfed by a double membrane to separate it from the rest of the cell; the resulting membrane-enclosed bubble of cytosol (along with all the proteins the bubble contains) becomes what is called the autophagosome. The autophagosome eventually fuses with a cellular organelle called a lysosome, a much larger membrane-enclosed bubble that contains a variety of enzymes that can break down many types of cellular components (which is why lysosomes are sometimes referred to as the “garbage disposals” of the cell). These enzymes only work in a very acidic environment, so the pH inside lysosomes is much lower than the neutral pH in the rest of the cell. This pH barrier, as well as the physical barrier of the organelle membrane, protects the rest of the cell from being degraded should the enzymes somehow leak out. Once the contents of the autophagosome are delivered to the lysosome, the lysosomal enzymes break down the new contents, which can then be recycled and reused within the cell.
Until a couple of years ago, it was believed that the main mechanism by which the nerve cell got rid of huntingtin aggregates involved what is called the ubiquitin-proteasome system, which is responsible for tagging and degrading improperly formed proteins. However, recent research shows that proteins with abnormally expanded stretches of the amino acid glutamine, like the altered huntingtin protein (which is associated with HD), are also disposed of by the process of autophagy. In this process, the aggregated proteins are gathered up and transported to the lysosome, where they are broken down and their component amino acids are recycled. Studies of nerve cells have shown that the mutant huntingtin protein can often be found in autophagosomes, the membrane-bound sacs that carry cell parts to the lysosome for degradation.
Researchers have investigated whether proteins with expanded sections of the amino acids glutamine and alanine could be degraded by cells using the process of autophagy. They compared autophagy with the ubiquitin-proteasome process, which was originally thought to be the only process by which these harmful proteins are degraded. The researchers used cells that expressed these proteins and tagged them with green fluorescent protein (GFP) in order to visualize their fate within the cells. GFP allows researchers to see the amount and the location of a specific protein present in the cell because it fluoresces, or glows, when viewed under a special microscope. To study how huntingtin aggregates are broken down by the cell, they used cells that produced, or expressed, part of the HD allele that contained either 55 or 74 CAG repeats. (To read more about the huntingtin protein, click here.)
To determine whether autophagy is indeed a key process in the clearance of huntingtin aggregates, the researchers first used two different compounds to inhibit autophagy at different points of the process and observed the effect on aggregate formation. The first compound they used inhibits autophagy by preventing a membrane from surrounding the cell contents that are about to be degraded; if the autophagosome cannot form, the contents cannot be delivered to the lysosome to be broken down. The second compound they used prevents the autophagosome from fusing with the lysosome and releasing its contents, which also prevents autophagy from occurring. Treatment with these compounds resulted in visibly higher levels of huntingtin aggregates in cell cultures, which showed that autophagy does play a role in the breakdown of aggregates. Along with the increase in aggregates, the researchers also saw increased cell death when the cells were treated with autophagy-inhibiting compounds.
The researchers also tested the role of the ubiquitin-proteasome system in reducing protein aggregation in the same cell cultures. Most previous experiments have used a certain compound to inhibit the proteasome that is thought to inhibit the function of the lysosome as well. Because they wanted to test the role of the proteasome only, the researchers used a different compound that inhibits the proteasome and has no effect on lysosomes. They found that inhibiting the proteasome increased aggregate formation in one cell line but not in another. While these results are somewhat inconclusive, they may suggest that the ubiquitin-proteasome process is not the main mechanism by which cells get rid of the disease-state huntingtin protein. More research about the role of autophagy in degrading mutant huntingtin needs to be done.
Several drugs are known to modulate the process of autophagy in different ways. The hope is that drugs which promote autophagy will aid nerve cells in breaking down huntingtin aggregates and help to protect the cells. Research is being done to identify the effectiveness of different types of drugs.
For further reading
Raught, et al. “The target of rapamycin (TOR) proteins.” Proceedings of the National Academy of Sciences of the United States of America. 2001 Jun 19;98(13):7037-44. Short paper which describes various functions of target of rapamycin (TOR) proteins in fairly technical writing.
Ravikumar, et al. “Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy.” Human Molecular Genetics. 2002 May 1;11(9):1107-17.
2001 Jun 19;98(13):7037-44. Fairly technical article which describes experiments aimed to discover whether or not proteins with multiple amino acid repeats could be controlled through the process of autophagy.
Ravikumar, et al. “Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease.” Nature Genetics 2004 Jun 36(6):585-95. This technical paper describing the effects of mTOR inhibition was cited in the “mTOR and HD” section.
Sarkar S., et al. “Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies.” Cell Death and Differentiation advance online publication, 18 July 2008; doi:10.1038/cdd.2008.110. Very technical paper which describes the effects of autophagy inducers in controlling HD and other diseases caused by malformed proteins.
Thoreen, et al. “Huntingtin aggregates ask to be eaten.” Nature Genetics. 2002 Jun;36(6):553-4. Less technical article that describes the role of autophagy in controlling mutant huntingtin aggregates.
Williams et al. “Novel targets for Huntington’s Disease in an mTOR-independent autophagy pathway.” 2008 May;5(4):295-305 Less technical article which reviewed the role of calpains in HD and different autophagy-inducing therapies was cited in the “Calpains and HD” and the “Combination Therapies” sections.
Inflammation, what we commonly know as the swelling, redness, heat, and pain that often accompany injuries, is one of our body’s most important natural defense mechanisms against internal and external threats. The inflammatory process protects our body from damage and disease by releasing cells and mediators that combat foreign substances and help prevent infection. However, these same inflammatory elements can also be deadly to the body when “switched on” too long, a condition known as chronic inflammation. Research has indicated that chronic inflammation is common in the nerve cells of patients with HD, and that it may be a powerful mediator of HD’s neurodegenerative damage.
Because the constant pain that often accompanies chronic inflammation is often a source of complaint in many diseases, there are a relatively large number of anti-inflammatory drugs and therapies available. However, most of these treatments target inflammation at a general level, and were not designed to block the inflammatory response specifically in the nerve cells affected by HD. As such, they can lead to unwanted side effects. The following anti-inflammatory drugs and supplements presented below have either the theoretical potential to alleviate inflammatory damage in the brains of patients with HD, or have been tested on other neurological diseases in which inflammation is a disease mechanism, such as Alzheimer’s disease. Some experiments and/or clinical trials of these treatments have been done on either animals or human patients with HD.
Important information about Huntington’s disease and inflammation
Studies of the HD brain indicate that long-term inflammation plays a significant role in the progression of HD. Given this finding, scientists are trying to understand the specific role of inflammation and are investigating the possibility of anti-inflammatory drugs as HD therapies.
The process of inflammation can be thought of as our body going into battle. Both inflammation and wars are responses to outside threats. Inflammation is a complex process that causes swelling, redness, warmth, and pain. It’s our body’s natural response to injury and plays an important role in healing and fighting infection. Similar to war, inflammation has its own troops: immune cells that secrete various molecules and enzymes that kill foreign invaders. Inflammation destroys and kills the injury-causing agent through a variety of mechanisms. Short-term inflammation protects the body from damage and disease. However, long-term or chronic inflammation, much like a drawn-out war, can lead to damage, not only to the foreign substances, but to the body itself as well.
Studies of the HD brain indicate that chronic inflammation plays a significant role in the progression of HD. Our body’s immune system has the ability to recognize foreign substances and launch various defense mechanisms to get rid of these potentially harmful substances. Scientists believe that the immune system recognizes the expanded glutamine tract in the altered huntingtin protein as “foreign” and tries to get rid of it, resulting in chronic inflammation and damage.
Studies have also shown that excitotoxic amino acids such as glutamate induce a direct activation and proliferation of cells involved in inflammation. Since glutamate activity is also implicated in the progression of HD, it is possible that the glutamate molecules in the HD brain induce an inflammatory response.
The inflammatory response results in the activation of various types of cells and the production of different molecules that can lead to cell death. An example of cells activated by the inflammatory response are the microglia (a type of immune cell) which have been found to be highly activated in the HD brain.
What are glial cells?
Nerve cell bodies and axons are surrounded by glial cells. Glial cells outnumber nerve cells by about five to one in the nervous system. Although their names come from the Greek word for glue, glial cells do not actually hold other cells together. Furthermore, glial cells do not conduct nerve impulses, and are thus not essential for processing information. Rather, they serve as supporting elements to the brain and act as scavengers, removing debris after injury or neuronal death. Two types of glial cells produce the fatty coating that covers large axons of the nerve cells.
There are many different types of glial cells in the nervous system. Glial cells such as the oligodendrocytes produce the fatty coating in nerve cells, the astrocytes maintain ionic balance, while the microglia get rid of unwanted substances.
Glial cells and HD
Research has shown that there is a marked increase in microglia in the HD brain. Microglia play the role of immune cells in the brain. They are sometimes called “brain macrophages” because they perform many of the same functions that macrophages in our body do. Macrophages are immune cells found all over our body that act as scavengers, engulfing dead cells, foreign substances, and other debris.
In the brain, the microglia act as macrophages, getting rid of unwanted substances by engulfing them and “eating” them.
Microglia are normally inactive. They become active in the brain following a variety of debilitating events such as infection, trauma, and decreased blood and oxygen flow. Once activated, the microglia are then able to remove dying neurons and other cells.
In the HD brain, an increase in activated microglia is found along the vicinity of nerve cells that contain neuronal inclusions (NIs) – accumulation of the huntingtin protein. This finding suggests that the huntingtin protein accumulation influences the activation of reactive microglia. Nerve cell injury due to excitotoxins such as glutamate also induces long-term microglial activation in the brain. Excitotoxins are excitatory amino acids found in increased concentrations in the nervous system and cause damage and cell death. (For more on excitotoxins, click here.)
Microglia and other inflammatory mediators
Aside from engulfing foreign substances, activated microglia are also capable of producing various substances that act as mediators of the inflammatory response. Although these mediators play an important role in inflammation, they are also potentially neurotoxic substances that can contribute to widespread central nervous system injury. Examples of inflammatory mediators include free radicals, proteases, excitatory amino acids, complement proteins, cytokines, and certain prostaglandins. These substances are the microglia’s “weapons”: they act to kill the foreign substance that invade our body. However, as stated before, chronic inflammation results in chronic release of these substances, which can eventually lead to considerable damage and cell death.
The exact mechanisms of these substances are not covered in this section. More information on each of the various inflammatory mediators can be found in various sources listed in the references section.
These mediators each have different roles in the inflammatory response, but for our purposes, it is sufficient to know that all of them contribute to inflammation and are found in increased concentrations in the brains of people with neurological diseases such as HD and AD. Drugs that could lower the concentrations of these molecules are therefore attractive treatment agents for people with diseases where inflammation plays a prominent role.
Inflammation and disease
Inflammation, whether in the brain or in other parts of the body, is almost always a secondary response to some primary disease-causing substance or event. Despite the fact that inflammation is a secondary response, it is still an important mechanism that can protect or damage the cell, depending on its severity and length of occurrence. In head trauma, for example, the blow to the head is the primary event. However, what may be of greater concern is the secondary inflammatory response that will result from the primary event. When it continues for a long period of time, inflammation is likely to cause more neuron loss than the initial injury. Given that chronic inflammation has been reported in the brains of people with HD, anti-inflammatory compounds that will delay the inflammatory response or eradicate it altogether may be potential HD treatments to consider.
Various inflammatory mediators are released by our immune cells during times when harmful agents invade our body. Long-term release of some of these inflammatory mediators has been observed in the cells of people with HD. An understanding of how these mediators work and how to block their release could be helpful in looking for ways to delay the progression of HD.
Our body must defend itself against many different disease-causing substances such as viruses, bacteria, and parasites, as well as tumors and a number of various harmful agents. To combat these disease-causing substances or events, our body has developed many mechanisms to defend itself against such an “attack.” One of the ways by which our body protects itself is by triggering an inflammatory response. Early scientists considered inflammation as our body’s primary defense system. However, inflammation is more than just a simple defense system, because when left unchecked, it could lead to debilitating diseases such as arthritis or even death. Long-term inflammation is also linked to the progression of neurological diseases such as Alzheimer’s Disease and Huntington’s Disease.
The development of inflammatory reactions is controlled by various molecules released by our body’s immune cells. Our immune cells act as the body’s “soldiers”, and they guard the body against attack by releasing “weapons” in the form of inflammatory mediators. One type of immune cell found to be present in extraordinarily high concentrations in the HD brain is the microglia. The microglia have been observed to release various inflammatory mediators that contribute to the long-term occurrence of inflammation in the HD brain, resulting in damage and cell death.
We will go over some of the most common inflammatory mediators released by the body’s immune cells in order to understand how the inflammatory response works. In general, most of the mediators that we will talk about in this section have one of two roles: amplification of the immune response, or destruction of the foreign substance.
This section will discuss the following inflammatory mediators: Free Radicals, Excitotoxins, Complement, Cytokines, Prostaglandins.
Free radicals are atoms or molecules that are highly reactive with other cellular structures because they contain unpaired electrons. As free radicals react with cellular structures, they lead to cellular injury and eventually, cell death. Free radicals may also trigger activation of various proteins that in turn activate the inflammatory response.
Although the majority of the research on HD focuses on free radical generation due to impaired electron transport chain functioning, the concept of free radical toxicity actually has its roots in inflammation biology. (Click here for more information on free radicals and antioxidants.) The secretion of reactive oxygen and nitrogen free radical species by inflammatory cells is a major mechanism for attacking foreign substances. Large amounts of free radicals are produced by activated microglia, and chronic release of free radicals result in neuronal injury and cell death.
Excitotoxins such as glutamate and quilonic acid are excitatory molecules that are released by immune cells and are known to cause damage to the body. They can also result in cognitive impairment when found in increased concentrations in the brain. Glutamate has specifically been found to initiate various mechanisms that ultimately lead to cell death. (For more information on glutamate, click here.)
Complement is a set of many proteins activated in sequence when cells are exposed to a foreign substance. Once the proteins are activated, nine of them come together to form the membrane attack complex (MAC). When assembled on a cell membrane, MAC forms a ring-like structure that allows the movement of ions and small molecules into and out of the cell, disrupting the normal state of the cell.
The MAC creates a pore that allows the movement of various ions and substances into and out of the cell, resulting in cell damage.
The complement system is a potent mechanism for initiating and amplifying inflammation. One of the most damaging effects induced by the formation of MAC is the entry of calcium ions (Ca2+) into the cell. The Ca2+ ions are capable of activating various Ca2+-dependent proteins that contribute to cell death. If a sufficient number of MACs have assembled on the cell, cell death eventually occurs.
Studies have reported that a number of complement proteins are expressed at a higher level in HD brains compared to non-HD brains. The increased number of activated microglia induced by the altered huntingtin protein most likely causes the higher levels of complement proteins in HD brains.
Cytokines are proteins that are secreted by various types of immune cells and serve as signaling chemicals. The central role of cytokines is to control the direction, amplitude, and duration of the inflammatory response.
There are two main groups of cytokines: pro-inflammatory and anti-inflammatory. Pro-inflammatory cytokines are produced predominantly by activated immune cells such as microglia and are involved in the amplification of inflammatory reactions. Anti-inflammatory cytokines are involved in the reduction of inflammatory reactions. Table 1 lists some of the most common proinflammatory and inflammatory cytokines.
Table 1: List of common pro-inflammatory and anti-inflammatory cytokines
Prostaglandins are produced in most tissues of the body and have varying actions. They are short-lived, hormone-like chemicals that regulate cellular activities on a moment-to-moment basis. Prostaglandins fall into 3 series – PG1, PG2, and PG3. PG1 and PG3 are known to have anti-inflammatory effects as they decrease inflammation, increase oxygen flow, prevent cell aggregation, and decrease pain. PG2 are known to have pro-inflammatory effects, since their effects are opposite to those of PG1 and PG3. Table 2 shows a comparison of the effects of the different prostaglandins.
PG1 and PG3 (anti-inflammatory)
Increase oxygen flow
Decrease oxygen flow
Table 2: Prostaglandins
Because of the negative effects of chronic inflammation, it is speculated that people with HD would most likely benefit from an increase in Series 1 and 3 prostaglandins and a decrease in Series 2 prostaglandins.
For further reading
Neuroinflammation Working Group. “Inflammation and Alzheimer’s Disease.” Neurobiology of Aging. 2000; 21: 383-421. This article contains detailed, comprehensive information on the inflammatory response and Alzheimer’s Disease (AD). It has information on the many studies done on the role of inflammation on the pathology of AD as well as the trials conducted on various anti-inflammatory compounds.
Sapp, et al. “Early and Progressive Accumulation of Reactive Microglia in the Huntington Disease Brain”.Journal of Neuropathology and Experimental Neurology. 2001; 60(2): 161-172. This article contains information on a study done that investigated the presence of reactive microglia in postmortem brains of people with HD. The study reported that increased levels of reactive microglia are present in HD brains.
Singhrao, et al. “Increased Complement Biosynthesis By Microglia and Complement Activation on Neurons in Huntington’s Disease.” Experimental Neurology. 1999 Oct; 159(2):362-376. This article contains the full details on a study done to investigate the levels of inflammatory response proteins in HD nerve cells. The study reported that increased levels of those proteins are found in HD nerve cells.
Glutamate is a powerful excitatory neurotransmitter that is released by nerve cells in the brain. It is responsible for sending signals between nerve cells, and under normal conditions it plays an important role in learning and memory
Individuals at risk for Huntington’s disease (HD) have the option of undergoing genetic testing, which detects the presence or absence of the genetic sequence that causes HD. The decision of whether or not to undergo genetic testing is intensely personal, with many factors to consider. This chapter will provide scientific background information regarding genetic testing for Huntington’s disease.
Let’s start with the basics of genetics. The word “genome” refers to an organism’s complete set of DNA. The fundamental building block of our genome is the molecule known as DNA. You’ve no doubt heard of DNA many times before – in the news, in movies, on television. Yet in order to understand Huntington’s disease, it is important to gain a good understanding of DNA and how DNA is related to genes. Our goal in this section is to review the basic features of the structure and function of the main molecule of heredity.
What causes the onset of HD? Current research shows that there is an abundance of information to be learned regarding the genetic origins of HD. Let’s trace HD’s beginnings from the molecular level, exploring the relationships between a gene, a protein, aggregation “clumps,” neural cell death, and the disease itself.
In order to make predictions about the future spread or decline of Huntington’s Disease, we can draw upon scientific tools from the field of population genetics (see Part I for an introduction to this field).
With their sword-wielding, karate-chopping, and pizza-eating ways, the Teenage Mutant Ninja Turtles swept American children by storm in the early 1990s. Unfortunately, though they did get kids to sit still for 30 minutes each day, the turtles also contributed to a widely held public misconception about what it means to have a mutation. From watching their television program, one might think that people with mutations will grow green skin and begin a new life in the city’s sewer pipes. In reality, though, there is nothing out of the ordinary about mutations. In fact, every person in the entire world has some sort of mutation in his or her DNA; in that sense, everyone is a mutant! Mutations are not just normal, they are important: evolution itself cannot occur without mutations.
Humans spend an extraordinary amount of their lives asleep. If you sleep eight hours every night, you will have spent one third of your entire life sleeping. But like coffee or cell phone reception, sleep is one of the most basic aspects of everyday life that you probably take for granted—when you are well-rested, you probably do not think about sleep much, but after you have pulled an all-nighter (or two), you are likely to have a keen perception of your body’s intrinsic drive to go to sleep. Although the necessity of sleep is intimately known, the scientific understanding of sleep is still very much incomplete. Scientists know that sleep is common to a wide range of organisms from the very complex, like humans, to the very simple, like worms. The shared need for sleep across distant branches of the evolutionary tree suggests that sleep serves some basic purpose. However, scientists still have yet to answer many fundamental questions about sleep: Why do organisms need to sleep? What are the molecular and cellular mechanisms that underlie sleep? What are the genes that contribute to sleep disorders?
The importance of sleep
Experiments in animal models have suggested that sleep is necessary for the survival of a great variety of different organisms. Multiple studies have shown that rats deprived of REM sleep (see next section) die within four to six weeks, while those completely deprived of sleep only survive two to three weeks. Sleep deprivation had a marked physical effect on these rats. The animals that were not allowed to sleep exhibited increased weight loss, decreased body temperature, impaired immune systems, progressive hair discoloration, and the appearance of skin lesions. But even with these obvious signs of deterioration, scientists still were not able to pinpoint the exact cause of death in these sleep-deprived rats. Although scientists could correlate the rapid deterioration of these animals to their total sleep deprivation, they could not identify a distinct chemical or physiological abnormality that ultimately doomed these rats.
Despite the dramatic effects of sleep deprivation in rats, similar physiological symptoms under laboratory conditions have not been observed in humans, as equivalent tests cannot be run on human subjects. Regardless, sleep loss does have recognizable and measurable effects on human cognitive function, motor performance, and mood. These negative effects can be dangerous, especially when sleep deprived individuals are engaging in attention-dependent activities such as driving, medical care and similar tasks that require critical thinking and reasoning. Sleep deprivation also impairs higher brain functions, including memory formation, verbal fluency, and creativity. The effects of sleep deprivation can be powerfully seen in fatigue-related car accidents. For example, truck drivers who have been on the road for thirteen hours straight are fifteen times more likely to have a fatal car crash in the thirteenth hour than the first hour. In fact, many researchers have suggested that the effects of driving while sleepy can be comparable to driving when drunk. Not getting enough sleep on a consistent basis can result in the buildup of a sleep “debt” that will negatively impact attention, performance, and health.
What happens during sleep
There is a common conception that sleep is for rest, a period during which the mind and body can rejuvenate after a hard day’s work. This assumption is not unfounded—during sleep, humans are less responsive and less mobile, not dissimilar to other states of unconsciousness such as coma (but unlike comas, sleep is rapidly reversible). However, sleep is a time of significant brain activity that can be observed using a machine known as an electroencephalogram (EEG). By hooking up many different electrodes to the scalp of a patient, researchers can measure the electrical activity that takes place in the brain during sleep. Sleep is also measured by observing eye movements, which closely correlate to the type of brain waves observed in the EEG.
The two main states of sleep have been defined as non-rapid eye movement (NREM) and rapid eye movement (REM). During NREM sleep, neuronal activity in many parts of the brain is decreased, and the waves that appear on the EEG are characteristically slower than waking states. In addition, this sleep stage is accompanied by noticeable physiological changes, including the increased secretion of growth and sex hormones and decreased motor activity, heart rate, metabolic rate, breathing rate, blood pressure and intestinal mobility. Conversely, scientists have found that during REM sleep, brain waves are similar to those observed when humans are awake. This raises the interesting question: if neuronal activity is so similar in periods of both REM sleep and wakefulness, what accounts for the drastic differences between these two states? It has been suggested that a small number of neurons are responsible for differentiating between REM sleep and waking. REM sleep is characterized by pupil constriction and rapid movement of the eyes. Accompanying physiological responses include irregular heart rate, breathing and blood pressure. In addition, REM sleep is also when human dreams occur, which have been described as intense bursts of activity in certain populations of neurons. Throughout the night, the brain will alternate between periods of REM and NREM sleep every 90 minutes, repeating this cycle five to six times every night. Although both REM and NREM periods will occur during this 90 minute time window, the proportion of REM to NREM sleep increases during the night. NREM sleep dominates just after falling asleep, while periods of REM sleep dominate in the later sleep cycles.
Despite the well-characterized neurological and physiological changes that occur during sleep, scientists are still in disagreement over the actual purpose of both NREM and REM sleep in humans. Current theories include: reducing the energy consumption of the brain, consolidating memory, promoting neural plasticity (for more information on neural plasticity, click here), and increasing the body’s synthesis of important cellular building blocks such as proteins. Even though there have been many experiments showing that sleep is correlated with these various functions, scientists have found it very difficult to develop a unified theory of why we sleep. Part of this can be attributed to weaknesses in the empirical evidence—even if certain effects are statistically significant, they are not particularly notable. For example, although research has shown that exercise can improve sleep, this is only by about 10 minutes per night. In addition, sleep research is conducted with a variety of different methods in a variety of organisms, further confounding efforts to build a unified theory of sleep. After all, the chemistry, physiology and function of sleep could very well differ significantly between similar organisms.
Sleep and circadian rhythm
You probably know from experience that your body responds differently depending on the time of the day. For example, you likely find it much easier to fall asleep at night than in the middle of the day. This is because darkness activates your body’s production of melatonin, a hormone that promotes sleep. Indeed, the entire human body runs on a 24-hour cycle of wakefulness and sleep. This so-called circadian rhythm (circa-, “approximately,” –diem, “day”) is driven by pacemaker cells in the hypothalamus, the part of your brain that controls a range of vital functions, including hunger, thirst, blood pressure and body temperature. Your circadian rhythm not only controls when you are alert and when you are tired, but it also coordinates your body’s countless chemical reactions. For example, during the day, when your blood sugar levels are likely to be high from eating, your body activates the chemical reactions that break down sugar into stored energy. Conversely, during the night, when your blood sugar is likely to be low, the specific processes that create sugar from stored energy are activated. The effects of the circadian pacemaker can also be seen at a whole-organism level. Human alertness and performance is highest during the day and lowest in the hours before daylight (3:00 – 6:00am), correlating with the time that humans are likely to be awake and asleep. Additionally, immediately after waking, you have probably experienced a good period of time when you were groggy and not alert. This span of time is known as sleep inertia and can last for hours after you get up. In opposition to this sleep inertia, the circadian clock sends out wake-promoting signals throughout the day, which counteracts the propensity to go back to sleep. The opposite process happens at night, with sleep-inducing signals eventually overpowering the wake-promoting ones, resulting in sleep. This natural cycle of sleep/wake signals, driven by the circadian rhythm, explains why humans tend to sleep more efficiently at night and less efficiently during the day.
It is becoming clearer that when you sleep may be just as important as how much you sleep. Deviating from your body’s circadian rhythm can lead to neurological and physical problems. Research has shown that shift workers with jobs that require them to be awake at night (e.g. police officers, fireman and health care providers) are more likely to suffer from diminished performance, sleep issues, and stress-related disorders than those who work during the day. The latter two problems can lead to more-serious conditions such as high blood pressure, stroke and heart disease. Indeed, a report by the International Agency for Research on Cancer has concluded that shift work puts individuals at a higher risk for cancer, which may be a consequence of the cellular effects of circadian rhythm disruption.
Sleep disruption and Huntington’s disease
Given HD’s devastating effects on many different regions of the brain, it is perhaps unsurprising that the disease would have an effect on sleep. Although the striatum, the part of the brain most visibly affected by the disease, is not currently thought to play a large role in sleep regulation, Huntington’s disease does affect several regions that have been directly implicated in controlling sleep. For example, patients with HD have been shown to have significant atrophy of neurons in the hypothalamus, a region of the brain intimately involved in regulating metabolism and sleep/wake cycles. It is also possible that the sleep disturbances of patients with HD are secondary effects of other disease symptoms, such as depression and anxiety.
One survey on HD and sleep performed in Britain found that 87.8% of respondents suffered from sleep problems, including restless limb movements, jerky movements, waking during the nighttime, early waking, and sleepiness during the day. These harmful symptoms have been correlated with many measurable sleep abnormalities. In a study performed by an international group of scientists, individuals with HD underwent nighttime sleep monitoring and daytime wakefulness examinations. These tests used a variety of instruments to measure sleep cycle progression, eye movements, brain activity and other physical indicators of sleep. When compared to the control group, individuals with HD spent more time in the light sleep stages (stages 1-2), experienced more periodic leg movements, and generally had lower sleep efficiency, the number of minutes spent in sleep divided by the number of minutes spent in bed. In addition, individuals with HD have been shown to generally spend less time in REM sleep. Studies have shown that the long-term deprivation of REM sleep results in symptoms similar to those seen in acute sleep deprivation—impaired cognition, unstable moods and hormonal imbalances. These effects on REM sleep have been observed in individuals that were pre-symptomatic or otherwise had very mild symptoms, suggesting that problems with REM sleep are an early indicator for HD. It is noteworthy that other neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s, show similar sleep disturbances, suggesting that these illnesses may have similar effects on the neural networks that regulate sleep.
Because of the many detrimental effects of sleep deprivation on human health, scientists believe that the sleep disturbances associated with HD can exacerbate the disease. Indeed, many of the symptoms of sleep disorders are the same as the symptoms of Huntington’s disease, including the loss of motor control, memory problems, mood changes, and impaired cognitive function. Thus, disturbed sleep may be one of the mechanisms through which the behavioral, cognitive, and motor problems associated with HD develop. It is even possible that sleep deprivation is primarily responsible for some of the symptoms of HD, a hypothesis which remains to be tested. This raises the interesting possibility that treating sleep problems can improve the lives of those with HD. Research in R6/2 mice, a transgenic mouse model for HD, has shown that regulating the sleep of affected mice significantly improves their cognitive abilities. In these studies, affected mice were given a sedative to help them fall asleep during the day, and then a wake-promoting drug to help these mice stay awake at night (normally, mice are asleep during the day and awake at night). Compared to the untreated mice, the R6/2 mice that had their sleep/wake cycles regulated by drugs showed improved performance in a series of cognitive tasks. The authors hypothesized that these beneficial effects could be due to restoration of the mice’s circadian rhythms, and that sleep therapy could one day be used to slow the progression of neurodegenerative diseases such as HD. Another important benefit of sleep therapy could be for the caretakers of those with Huntington’s disease. Several studies have found that difficulty dealing with nocturnal sleep problems is one of the most common reasons that caretakers choose to institutionalize patients with neurodegenerative disease.
Although these mice studies are promising, the effects of sleep regulation on humans with HD have yet to be studied. However, the evidence so far indicates that sleep therapy might not only improve the symptoms of HD, but may even affect the progression of the disease. And the fact remains that we could all probably use some more sleep!
Arnul, I. et al. (2008). Rapid eye movement sleep disturbances in Huntington disease. Archives of Neurology 65(4): 482-488.
This article presents the results of a study examining REM sleep problems in patients with HD. The introduction and comment section are quite informative and very readable.
Goodman, A. & Barker, R.A. (2010). How vital is sleep in Huntington’s disease? Journal of Neurology 257(6): 882-897.
This eminently-readable article provides an excellent review of the evidence relating disturbed sleep with Huntington’s disease.
Pallier, P. & Morton, J. (2009). Management of sleep/wake cycles improves cognitive function in a transgenic mouse model of Huntington’s disease. Brain Research 1279: 90-98.
This primary source presents the results of experiments assessing the effects of drug-induced sleep therapy on mice model of HD. The introduction and conclusion are quite interesting and generally quite understandable.
Rechtschaffen, A. (1998) Current perspectives on the function of sleep. Perspectives in Biology and Medicine 41(3): 359-391.
This article offers a comprehensive review on the function of sleep. Although the writing is slightly technical, it is still quite useful and comprehensible.
Reddy, A. & O’Neill, J. (2009). Healthy clocks, healthy body, healthy mind. Trends in CellBiology 20(1): 36-44.
This review talks about the importance of circadian rhythms. The article is quite technical.
Siegal, J. (2005). Clues to the functions of mammalian sleep. Nature 437: 1264-1271.
This review article presents some of the current theories and analyzes some of the existing evidence regarding the importance of sleep in mammals. The writing is technical, but the main points are relatively accessible.
Zisapel, N. (2007). Sleep and sleep disturbances: biological basis and clinical implications. Cellular and Molecular Life Sciences 64: 1174-1186.
This very technical article gives a review of the many different problems associated with sleep disturbances.
Have you ever wondered where Huntington’s disease originated? Or why it’s predominantly found among Europeans and those of European descent? Population genetics, the study of the genetic makeup of populations and of changes over time in that makeup, attempts to answer such questions. In this chapter, we explore the origins of the HD allele, the variable frequency of HD around the world, and current theories for how the HD allele has “survived” through time in human populations.
Welcome to Stories of HOPES! The short stories of this section of HOPES are fictional accounts inspired by the experiences of real families living with HD. They are not meant to be instructive or prescriptive, but to serve as artistic impressions of the social and familial impact of the disease. We have found them a useful way to stimulate discussion of HD and its implications with others. As always, we invite your comments on these stories.
– The Staff of HOPES
Bryan’s Dad is a story of a father becoming symptomatic for HD and the complexity of a family’s experience when dealing with the signs and diagnosis.
JHD Short Story Series is a series of fictional short stories from the perspective of someone with JHD. These works do not represent the experience of any one individual, nor do they aim to encompass the entirety of an illness experience such as JHD. Rather, these stories strive to capture and explore themes presented across different JHD and HD experiences through a collection of punctuated narratives. Hopefully, engaging with JHD through storytelling will allow readers to better empathize with, and understand the nature of, the experience of this illness.
Maladies of My Mind is a five chapters fictional account of a surgeon in Thailand and how she struggles to come to terms with the possibility of carrying the gene for an incurable neurodegenerative disease in a country where mental illness is a stigma. This story is inspired by interviews of Thai individuals affected by different mental illnesses, but it does not cover the entirety of a Huntington’s disease experience in Thailand. However, it aims to explore themes of social stigma in a country where mental illness is not often talked about.
HOPES is excited to present a non-fictional story section on our website! This section is meant to be an open space in which individuals affected by Huntington’s disease (patients, caregivers, family members, and friends) can share their experiences with HD in the form of anonymous text excerpts. We believe the sharing of narrative can have healing qualities and promote connectivity within the greater HD community.
SNAPSHOTS is inspired by the notion that without lived experience, it is often difficult to see more than mere glimpses into the lives of patients, caregivers, and loved ones affected by HD. This series of images and stories attempts to show more realistic glimpses into the inspirational life stories of those affected by HD.
Caregivers: Get a Dog! is a story about one couple’s positive experiences with dog adoption in the face of diagnosis.
After The Diagnosis is a short piece about the process of acceptance after receiving news of an HD diagnosis.
The Bar Exam is a story that masterfully compares one individual’s genetic test with the Bar Exam she took after law school.
Stories can take the form of submitted text or transcribed, in-person interview. We are open to all forms and styles of writing. If you are interested in submitting a story or setting up an interview, please contact HOPES member Annie Rempel (firstname.lastname@example.org).
Downloading files saves a copy of the file onto your computer so you can view it later on your own, even when you are away from the internet. In addition, for users using a slower dial-up (modem) internet connection, downloading large files may be especially useful, because a dialog box should always appear that gives information on the status of the download (% completed, estimated time left, etc.).
To download a particular file, right-click on the appropriate link. A menu will appear with several options. Select "Save Target As" (in Internet Explorer) or "Save Link Target As" (in Netscape Navigator or Mozilla). Note that while these images show the downloading process for Internet Explorer, similar menus and dialog boxes will appear in Navigator or Mozilla.
A "Save As" dialog box will then appear. Choose the location in which you would like to save your file. Make sure that it is a location that you will remember and that is easy to locate. Type in your own filename or reuse the one we've offered, and then click "Save".
The next dialog box appears while the file is being downloaded. The progress bar and % Completed keep you updated on the downloading process. Most browsers give you some indication of the estimated time left for downloading, taking into account the file size and the speed of your internet connection, although it should be noted that this estimation is rough.
When the file is finished downloading, the % Completed changes to the following dialog box. You can then view the file immediately by clicking "Open". Click "Close" to close the dialog box and continue surfing.
In order to view media files directly in one's browser, the appropriate plug-in must be installed. Luckily, most programs that are designed for internet media (such as Macromedia Flash, Adobe Reader, QuickTime, Windows Media, etc.) will automatically install a plug-in into your browser. In these cases, simply left-clicking on a link will allow a user to view the file directly in his or her browser window. (In cases where the appropriate plug-in is not installed, left-clicking a particular link will simply download the file in the same fashion as a user right-clicking a link. See above for a description of the downloading process.)
If neither of these options allow you to view the files correctly, you probably do not have the appropriate program installed. Click here for more information.
Some of the content at HOPES can only be viewed in certain applications separate from the usual web browser. Because most of these programs are designed specifically for web use, they are often referred to as "plug-ins" because they usually install a small program that can operate directly within one's browser if asked to do so.
If you are having trouble viewing certain content or files at HOPES, you likely do not have the appropriate plug-in installed. Also, be aware that plug-ins often go through revisions, so a plug-in that you thought was already installed may be out of date and require updating. The table below lists the all of the plug-ins that you may need to view HOPES content correctly.
All of these plug-ins are available for most current operating systems for both PCs and Macs. Nearly all are provided for free unless otherwise stated. Also, many of the plug-ins will open other file types besides the one(s) mentioned. Consult the appropriate websites for more information.
Feel free to contact HOPES with questions or comments. However, we emphasize that we are not computer technicians and can only provide some support for plug-in issues.
**MS Word is not a free plug-in and cannot be purchased. However, nearly all current word processors have some translator that allows you to view .doc files.
The X-Linked Inhibitor of Apoptosis Protein (XIAP) gene is a gene present in normal body cells that inhibits the activity of caspases 9, 3, and 7. A caspase is an enzyme that degrades proteins and is involved in certain types of cell death, also known as apoptosis. In Huntington’s disease (HD), the presence of mutant huntingtin clumps, or aggregates, activates caspases. Once a caspase is activated, it can cut mutant huntingtin protein into smaller pieces, making the mutant huntingtin protein more toxic and causing brain cells to die. Remember that some evidence exists that apoptosis of brain cells is the root of the neurodegenerative problems in HD. To learn more about cell death in HD, click here.
Because the XIAP gene inhibits caspase activity, it can prevent cell death, which means it has great potential in the treatment of neurodegenerative diseases such as HD. The goal of XIAP gene therapy is to inject this gene into cells that are affected by HD so that apoptosis does not occur.
How has XIAP gene therapy been shown to prevent apoptosis?
In 2005, researchers working for the pharmaceutical company Neurologix Incorporated tested the potential of the XIAP gene both in vitro (outside of a living organism) and in vivo (inside of a living organism). In vitro, the scientists added the XIAP gene (also known as dXIAP) to brain cells that were designed to have the HD mutation. The study found that the addition of dXIAP significantly decreased the number of cells that died due to apoptosis. The scientists also confirmed the potential of XIAP gene therapy in rat models. The rats were engineered to have symptoms of Parkinson’s disease, a disease that, like HD, results in brain cell death. Researchers found that the neurons of rats that were injected with dXIAP were protected against apoptosis.
In the same study, the scientists also aimed to determine more specifically how XIAP gene therapy works. To do this, they engineered four mutant versions of the dXIAP gene. In each mutant version, a different small section of the gene was mutated so that its function was disrupted. Each of these mutant versions was injected into HD-mutant cells to test their effectiveness. The scientists found that only a mutation in a section called BIR3 prevented dXIAP from effectively stopping cell death. This means that the BIR3 section, specifically, is most crucial to the success of XIAP gene therapy. This was useful because the scientists already knew that the BIR3 domain commonly interacts with caspase 9. Thus they concluded that the neuroprotective effect of the XIAP gene may primarily work by stopping the activity of caspase 9 rather than caspase 3 or 7.
What’s the potential of XIAP gene therapy in HD?
Neurologix Incorporated has taken the initiative to determine how the XIAP protein could be used to treat neurodegenerative symptoms in HD patients. In 2008, the company was given exclusive rights to use XIAP to develop a treatment for HD. As mentioned above, Neurologix has already shown that XIAP gene therapy has some effect in preventing cell death in rodents, but it is not yet ready to be tested in humans. Many more experiments with rodent models of HD have to be done before XIAP gene therapy can even be considered a possible treatment for HD in humans. Neurologix does plan to conduct clinical trials in humans, but it is unknown when they will be ready and able to begin these trials.
For Further Reading
Musatov, Sergei, Joshua Goldfein, Justin Fraser, John Pena, and Michael G. Kaplitt. “Neuroprotective Effects of XIAP Gene Therapy in Models of Neurodegenerative Diseases.” Molecular Therapy 11 (2005). Abstract.: n. pag. Print.
A journal article explaining the in vivo and in vitro pre-clinical trials of XIAP gene therapy to treat HD and Parkinson’s disease
“Neurologix Licenses to Aegera’ XIAP Gene for Use in Huntington’s.” GEN News Highlights. Genetic Engineering and Biotechnology News, 3 Sept. 2008. Web. 29 July 2009. <http://www.genengnews.com/news/bnitem.aspx?name=41256917>.
News article About Neurologix’s involvement in XIAP gene therapy studies
Sanchez Mejia, Rene O., and Robert M. Friedlander. “Caspases in Huntington’s Disease.” Neuroscientist 7 (2001): 480-89. Sage Journals Online. Web.
A journal article about the role of caspases in cell death in Huntington’s disease