What is the latest research on Huntington’s disease?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world. The NINDS conducts and supports research to better understand and diagnose Huntington’s disease (HD), develop new treatments, and ultimately, prevent HD. The NINDS also supports training for the next generation of HD researchers and clinicians, and serves as an important source of information for people with HD and their families.

NINDS-funded research has played a key role in our understanding of HD—helping to localize the HD-causing gene to chromosome 4 and identifying the mutation that causes HD. These findings have proven invaluable for diagnosis and research, and have enabled neuroscientists to create animal models of the disorder. Signs of HD have been reproduced in fruit flies, mice, and non-human primates by giving the animals one or more copies of the HD mutations found in people. These models are used to study mechanisms of the disease, to identify potential therapeutic strategies, and to move forward with those strategies most likely to work and least likely to cause harm for individuals. Just as important, the gene discovery enables neurologists to recruit individuals who carry the HD gene into clinical studies early—before they become ill.

The HD Gene

How do mutations in the HD gene lead to neuronal degeneration? The normal functions of the huntingtin (Htt) protein—the product of the HD gene—have yet to be fully defined, but may include regulating the development of the embryo, transport of molecules and organelles inside nerve cells, and controlling factors that support neuronal health. However, there is very strong evidence that the mutant Htt protein gains one or more new and harmful functions. A major focus of research on HD is to understand the toxicity of mutant huntingtin protein and to develop potential drugs for counteracting it.

People with HD have an abnormal, repetitive, greatly expanded three-letter code, called a CAG repeat, in their DNA sequence. DNA uses a threeletter code (or triplet) to prescribe the order and identity of amino acids—a protein’s building blocks. The triplet “CAG” designates the amino acid glutamine. The repeated CAGs in the normal HD gene are translated into a string of glutamines, called polyglutamine. The mutant HD gene codes for an abnormal form of the Htt protein with much longer polyglutamine repeats that are toxic to neurons. Also, the abnormal polyglutamine sequence affects how the huntingtin protein interacts with other proteins. At least eight other inherited neurological disorders are caused by polyglutamine expansions, each in a different gene.

RNA serves as an intermediate between DNA molecules and proteins; the genetic code within DNA is copied into RNA, which is then used as a template for making proteins. The mutant huntingtin protein RNA may itself be toxic to cells; its numerous repeats can attract and bind essential cellular proteins which thus become unavailable to perform their critical function in processing other RNA molecules from other genes.

NINDS is funding cutting-edge research that aims to eliminate or reduce the production of toxic HD-RNA and huntingtin protein. One potential therapy, called RNA interference, involves designing small bits of synthetic RNA to match, target, and destroy specific RNA molecules inside cells. Researchers have designed interfering RNAs that target HD-RNA and block the production of mutant huntingtin protein, and they have found this approach to be beneficial in mouse models of HD. Such synthetic RNA molecules called antisense oligonucleotides are being developed to be delivered into the cerebrospinal fluid. Others are packaging the RNA into viruses to deliver into the brain. Pharmaceutical companies are now initiating ambitious trials to test whether this approach may help people with HD.

Mutant Huntingtin Protein

Aberrant regulation of genes in HD. The abnormal interactions between mutant huntingtin protein and other proteins can have many adverse consequences, including altered gene regulation. Humans have approximately 20,000 genes, about one-third of which are active (or expressed) in the brain at some point in life. Precisely when and where these genes are expressed is controlled by a complex machinery within cells—and mutant Htt can upset this system. For instance, DNA in the cells of higher organisms is packed into chromatin—tight coils of DNA and small proteins called histones. Compounds that block gene expression and coiltightening activity of certain histones have been shown to counteract HD in animal models, and are attractive candidates for drug development. Other alterations in chromatin not only keep some necessary genes shut off, but mutant Htt can also inappropriately turn on other genes, such as those driving excessive inflammation, which damages and kills nerve cells in the brain.

Mutant Htt aggregation. Besides sticking to other proteins, mutant Htt has a tendency to stick to copies of itself and accumulate in clumps known as aggregates. These aggregates can pull in and block the activity of other proteins, and grow to form inclusion bodies—protein deposits inside cells that may overburden the cell’s ability to handle and dispose of old or damaged proteins. Neurons from different brain regions may differ in their efficiency of waste disposal. Neurons in the striatum, the brain region most affected in HD, show the slowest mutant huntingtin clearance rates, perhaps explaining their heightened susceptibility to the disease. Compounds that activate cellular waste handling systems have been shown to reduce the toxicity of mutant Htt in animal models. Recent evidence suggests that mutant huntingtin may also move from cell to cell in a person’s brain and induce aggregates and inclusions in neighboring cells, similar to what is seen in Alzheimer’s and Parkinson’s diseases.

Metabolism and mitochondria. Some studies suggest that mutant Htt interferes with the function of the tiny energy factories inside cells known as mitochondria. Others point to reduced efficiency of antioxidant pathways—protective pathways that scavenge harmful byproducts of brain activity that in normal conditions remain at innocuous levels. In HD some of these pathways are disrupted and the toxic byproducts accumulate to damaging levels. Drugs that inhibit the production of these harmful byproducts or accelerate their clearance have been designed and successfully tested in animal models. However, two NINDS-funded trials investigating any benefit of the metabolic supplements creatine and coenzyme Q10 in people with HD found no improvements in clinical symptoms at the doses tested.

Excitotoxicity, neural circuits, and survival factors. Researchers have yet to determine why Huntington’s disease has its most severe effects on neurons in the striatum, specifically on a cell type called mediumsized spiny neurons. One culprit may be the brain chemical glutamate, which is produced by neurons in the cerebral cortex and transmits information by exciting (signaling them to turn on) medium spiny neurons in the striatum. Excessive glutamate signaling between these cells may lead to overexcitation of medium spiny neurons in HD. Chronic over-excitation is toxic to neurons (called excitotoxity). Several labs are investigating whether drugs that counteract excitotoxicity might help against HD.

Some of the clinical symptoms in neurodegenerative diseases may be caused by the ultimate malfunctioning of neuronal circuits rather than by the loss of individual cells. Cutting-edge methods such as optogenetics (where neurons are activated or silenced in the brains of living animals using light beams) are being used to probe the cause and progression of such circuit defects in HD.

In addition to communications exchange, neurons may also provide each other with chemical signals (called trophic factors) that support the health and stability of neural circuits. Cortical neurons provide trophic support by releasing Brain Derived Neurotrophic Factor (BDNF), which supports the survival of medium spiny neurons in the striatum. Evidence suggests that mutant Htt suppresses the production of BDNF. Using animal models, researchers hope to restore BNDF-based trophic support to striatal cells and possibly prevent medium spiny neurons from dying.

Stem Cells

Stem cells are now a useful tool that helps us understand underlying molecular disease mechanisms.

Pluripotency—the ability of embryonic stem cells to become nerve, muscle, bone, and other cell types—depends on a unique genetic program that is typically shut off in adult cells. Scientists have discovered that it is possible to take adult blood or skin cells and, by activating this genetic program, return the cells to a pluripotent state (called induced pluripotent, or iPS, cells). Through an NINDS-funded consortium, individuals with HD have donated skin and blood samples for research, allowing the creation of iPS cell lines and iPSderived neurons for studying HD. Researchers are using cultures of these cell lines to understand why neurons malfunction and die in HD, and to rapidly test potential new drugs. Their aim is increase the efficiency of turning a person’s iPS cells into medium spiny neurons that reflect the human disease, and then to learn from these disease cells how the CAG-repeat expansion damages their function and viability.

Investigators are studying the effects of transplanting nerve cells derived from embryonic or adult stem cells (immature cells that eventually give rise to all of the body’s cell types) or fetal tissue. A number of small studies found no sustained improvement in transplanting fetus-derived cells into the striatum in people with HD.

In theory, induced pluripotent stem cells could be derived from a person with Huntington’s disease and then implanted into the person’s brain after correcting the HD mutation. However, brain function is dependent upon the correct connections between neurons and currently it is not known how to generate cells to form connections appropriately in a disease such as HD.

An alternative to transplanting stem cells into the brain may be to mobilize stem cells that are already there and shown to move into damaged tissue. Research on rodent models of HD suggests it might be possible to reawaken these cells by delivering specific growth factors to the brain. It is not yet clear whether this strategy will work in humans, as those with HD seem to have significantly fewer and less potent brain stem cells than healthy people.


The NINDS-funded PREDICT-HD study, as well as several international studies (such as REGISTRY, BIOHD, and Enroll-HD), seek to identify biomarkers for HD. Biomarkers are biological changes that can be used to predict, diagnose, or monitor a disease; for example, a sustained rise in blood sugar is a biomarker for diabetes. One goal of PREDICT-HD is to determine if the progression of the disease correlates with changes in brain scan images, or with chemical changes in blood, urine, or cerebrospinal fluid. Another goal is to find biomarkers characteristic of prediagnostic HD; measurable changes in personality, mood, and cognition that typically precede the appearance motor symptoms of HD.

A large and related NINDS-supported study aims to identify additional genetic factors in people that influence the course of the disease. Individuals with the same CAG expansions can differ widely in the age of disease onset and severity of symptoms. Researchers are trying to identify variations in the genomes of individuals with HD that account for those differences. Finding genetic variants that slow or accelerate the pace of disease progression promise to provide important new targets for disease intervention and therapy.

Clinical Studies

Studies of cognition, emotional functioning, and movement. Studies of motor problems (abnormal eye movements, chorea, and dystonia), psychiatric symptoms (apathy, psychosis, depression, and irritability), and tests of cognitive skills (learning and memory, attention, concentration, and executive functioning such as multitasking, problem-solving, and planning) may serve to identify when the symptoms of HD appear, and help characterize their range and severity as the disease progresses over time.

Clinical trials of drugs. Testing investigational drugs may lead to new treatments and at the same time improve our understanding of the disease process in HD. Classes of drugs being tested include those that control symptoms, slow the rate of progression of HD, block the effects of excitotoxins, provide support factors that improve neuronal health, or suppress metabolic defects that contribute to the development and progression of HD.

Imaging. Various imaging technologies allow investigators to view changes in the volume and structures of the brain, and to pinpoint when these changes occur in HD. Positron emission tomography (PET, which visualizes metabolic or chemical abnormalities in the brain) allows scientists to learn how HD affects the chemical systems of the brain. Investigators hope to learn if PET scans can reveal abnormalities that signal HD, as well as to characterize neurons that have died and chemicals that are depleted in parts of the brain of people with HD. Investigators are using functional MRI (fMRI), a form of magnetic resonance imaging that measures changes in the flow of blood-born chemicals known to correlate with brain activity, to understand how HD affects the functioning of different regions of the brain.

Brain structure. Altered brain development may play an important role in HD. Huntingtin is expressed during embryonic development and throughout life. Studies in animals have shown that the normal HD gene is vital for brain development. Adults who carry the mutant HD gene but have not yet displayed symptoms of the disease show measurable changes in the structure of their brain, even up to 20 years before onset of clinical diagnosis. It is not known when in life these changes become evident. One possibility is that the HD gene causes changes in early brain development that remain throughout life, and initially cause only subtle functional abnormalities.

In an effort to better understand how HD affects brain development, an NINDS-funded study is evaluating brain structure and function in children, adolescents, and young adults (ages 6-18) who are at risk for developing the disease because they have a parent or grandparent with HD. Participants who carry the expanded gene will be compared to individuals who carry the gene but have CAG repeats of 39 or less, as well as to individuals who do not have a history of HD in their family. Changes in brain structure and/or function in the gene-expanded group may point to a developmental component in HD.