Huntington Disease (cont.)
What research is being done on Huntington's disease?
Although Huntington's disease attracted considerable attention from
scientists in the early 20th century, there was little sustained
research on the disease until the late 1960s when the Committee to
Combat Huntington's Disease and the Huntington's Chorea Foundation,
later called the Hereditary Disease Foundation, first began to fund
research and to campaign for federal funding. In 1977, Congress
established the Commission for the Control of Huntington's Disease and
Its Consequences, which made a series of important recommendations.
Since then, Congress has provided consistent support for federal
research, primarily through the National Institute of Neurological
Disorders and Stroke, the government's lead agency for biomedical
research on disorders of the brain and nervous system. The effort to
combat
Huntington's disease proceeds along the following lines of inquiry, each
providing important information about the disease:
Basic neurobiology. Now that the Huntington's disease gene has
been located, investigators in the field of neurobiology-which
encompasses the anatomy, physiology, and biochemistry of the nervous
system-are continuing to study the
Huntington's disease gene with an eye toward understanding how it causes
disease in the human body.
Clinical research. Neurologists, psychologists, psychiatrists,
and other investigators are improving our understanding of the symptoms
and progression of the disease in patients while attempting to develop
new therapeutics.
Imaging. Scientific investigations using PET and other
technologies are enabling scientists to see what the defective gene does
to various structures in the brain and how it affects the body's
chemistry and metabolism.
Animal models. Laboratory animals, such as mice, are being bred in the hope of duplicating the clinical features of
Huntington's disease and can soon be expected to help scientists learn more about the symptoms and progression of the disease.
Fetal tissue research. Investigators are implanting fetal tissue
in rodents and nonhuman primates with the hope that success in this area
will lead to understanding, restoring, or replacing functions typically
lost by neuronal degeneration in individuals with
Huntington's disease.
These areas of research are slowly converging and, in the process, are
yielding important clues about the gene's relentless destruction of mind
and body. The NINDS supports much of this exciting work.
Molecular Genetics
For 10 years, scientists focused on a segment of chromosome 4 and, in
1993, finally isolated the
Huntington's disease gene. The process of isolating the responsible
gene—motivated by the desire to find a cure—was more difficult than
anticipated. Scientists now believe that identifying the location of the
Huntington's disease gene is the first step on the road to a cure.
Finding the Huntington's disease gene involved an intense molecular
genetics research effort with cooperating investigators from around the
globe. In early 1993, the collaborating scientists announced they had
isolated the unstable triplet repeat DNA sequence that has the
Huntington's disease gene. Investigators relied on the NINDS-supported
Research Roster for Huntington's Disease, based at Indiana University in
Indianapolis, to accomplish this work. First started in 1979, the
roster contains data on many American families with
Huntington's disease, provides statistical and demographic data to
scientists, and serves as a liaison between investigators and specific
families. It provided the DNA from many families affected by
Huntington's disease to investigators involved in the search for the
gene and was an important component in the identification of
Huntington's disease markers.
For several years, NINDS-supported investigators involved in the search
for the
Huntington's disease gene made yearly visits to the largest known
kindred with
Huntington's disease—14,000 individuals—who live on Lake Maracaibo in
Venezuela. The continuing trips enable scientists to study inheritance
patterns of several interrelated families.
The Huntington's disease Gene and Its Product
Although scientists know that certain brain cells die in Huntington's
disease, the cause of their death is still unknown. Recessive diseases
are usually thought to result from a gene that fails to produce adequate
amounts of a substance essential to normal function. This is known as a
loss-of-function gene. Some dominantly inherited disorders, such as
Huntington's disease, are thought to involve a gene that actively
interferes with the normal function of the cell. This is known as a
gain-of-function gene.
How does the defective Huntington's disease gene cause harm? The
Huntington's
disease gene encodes a protein—which has been named huntingtin—the
function of which is as yet unknown. The repeated CAG sequence in the
gene causes an abnormal form of huntingtin to be made, in which the
amino acid glutamine is repeated. It is the presence of this abnormal
form, and not the absence of the normal form, that causes harm in
Huntington's disease. This explains why the disease is dominant and why
two copies of the defective gene—one from both the mother and the
father—do not cause a more serious case than inheritance from only one
parent. With the
Huntington's disease gene isolated, NINDS-supported investigators are
now turning their attention toward discovering the normal function of
huntingtin and how the altered form causes harm. Scientists hope to
reproduce, study, and correct these changes in animal models of the
disease.
Huntingtin is found everywhere in the body but only outside the cell's
nucleus. Mice called "knockout mice" are bred in the laboratory to
produce no huntingtin; they fail to develop past a very early embryo
stage and quickly die. Huntingtin, scientists now know, is necessary for
life. Investigators hope to learn why the abnormal version of the
protein damages only certain parts of the brain. One theory is that
cells in these parts of the brain may be supersensitive to this abnormal
protein.
Cell Death in Huntington's disease
Although the precise cause of cell death in Huntington's disease is not
yet known, scientists are paying close attention to the process of
genetically programmed cell death that occurs deep within the brains of
individuals with
Huntington's disease. This process involves a complex series of
interlinked events leading to cellular suicide. Related areas of
investigation include:
- Excitotoxicity. Overstimulation of cells by natural chemicals found in the brain.
- Defective energy metabolism. A defect in the power plant of the cell, called mitochondria, where energy is produced.
- Oxidative stress. Normal metabolic activity in the brain that produces toxic compounds called free radicals.
- Trophic factors. Natural chemical substances found in the human body that may protect against cell death.
Several Huntington's disease studies are aimed at understanding losses
of nerve cells and receptors in
Huntington's disease. Neurons in the striatum are classified both by
their size (large, medium, or small) and appearance (spiny or aspiny).
Each type of neuron contains combinations of neurotransmitters.
Scientists know that the destructive process of
Huntington's disease affects different subsets of neurons to varying
degrees. The hallmark of
Huntington's disease, they are learning, is selective degeneration of
medium-sized spiny neurons in the striatum. NINDS-supported studies also
suggest that losses of certain types of neurons and receptors are
responsible for different symptoms and stages of
Huntington's disease.
What do these changes look like? In spiny neurons, investigators have
observed two types of changes, each affecting the nerve cells'
dendrites. Dendrites, found on every nerve cell, extend out from the
cell body and are responsible for receiving messages from other nerve
cells. In the intermediate stages of
Huntington's disease, dendrites grow out of control. New, incomplete
branches form and other branches become contorted. In advanced, severe
stages of
Huntington's disease, degenerative changes cause sections of dendrites
to swell, break off, or disappear altogether. Investigators believe that
these alterations may be an attempt by the cell to rebuild nerve cell
contacts lost early in the disease. As the new dendrites establish
connections, however, they may in fact contribute to nerve cell death.
Such studies give compelling, visible evidence of the progressive nature
of
Huntington's disease and suggest that new experimental therapies must
consider the state of cellular degeneration. Scientists do not yet know
exactly how these changes affect subsets of nerve cells outside the
striatum.
Animal Models of Huntington's disease
As more is learned about cellular degeneration in Huntington's disease,
investigators hope to reproduce these changes in animal models and to
find a way to correct or halt the process of nerve cell death. Such
models serve the scientific community in general by providing a means to
test the safety of new classes of drugs in nonhuman primates.
NINDS-supported scientists are currently working to develop both
nonhuman primate and mouse models to investigate nerve degeneration in
Huntington's disease and to study the effects of excitotoxicity on nerve
cells in the brain.
Investigators are working to build genetic models of Huntington's
disease using transgenic mice. To do this, scientists transfer the
altered human
Huntington's disease gene into mouse embryos so that the animals will
develop the anatomical and biological characteristics of
Huntington's disease. This genetic model of mouse Huntington's disease
will enable in-depth study of the disease and testing of new therapeutic
compounds.
Another idea is to insert into mice a section of DNA containing CAG
repeats in the abnormal, disease gene range. This mouse equivalent of
Huntington's disease could allow scientists to explore the basis of CAG
instability and its role in the disease process.
Fetal Tissue Research
A relatively new field in biomedical research involves the use of brain
tissue grafts to study, and potentially treat, neurodegenerative
disorders. In this technique, tissue that has degenerated is replaced
with implants of fresh, fetal tissue, taken at the very early stages of
development. Investigators are interested in applying brain tissue
implants to
Huntington's disease research. Extensive animal studies will be required
to learn if this technique could be of value in patients with
Huntington's disease.
Clinical Studies
Scientists are pursuing clinical studies that may one day lead to the
development of new drugs or other treatments to halt the disease's
progression. Examples of NINDS-supported investigations, using both
asymptomatic and symptomatic individuals, include:
Genetic studies on age of onset, inheritance patterns, and markers found
within families. These studies may shed additional light on how
Huntington's disease is passed from generation to generation.
Studies of cognition, intelligence, and movement. Studies of abnormal
eye movements, both horizontal and vertical, and tests of patients'
skills in a number of learning, memory, neuropsychological, and motor
tasks may serve to identify when the various symptoms of
Huntington's disease appear and to characterize their range and
severity.
Clinical trials of drugs. Testing of various drugs may lead to new
treatments and at the same time improve our understanding of the disease
process in
Huntington's disease. Classes of drugs being tested include those that
control symptoms, slow the rate of progression of
Huntington's disease, and block effects of excitotoxins, and those that
might correct or replace other metabolic defects contributing to the
development and progression of
Huntington's disease.
Imaging
NINDS-supported scientists are using positron emission tomography (PET)
to learn how the gene affects the chemical systems of the body. PET
visualizes metabolic or chemical abnormalities in the body, and
investigators hope to ascertain if PET scans can reveal any
abnormalities that signal
Huntington's disease. Investigators conducting Huntington's disease
research are also using PET to characterize neurons that have died and
chemicals that are depleted in parts of the brain affected by
Huntington's disease.
Like PET, a form of magnetic resonance imaging (MRI) called functional
MRI can measure increases or decreases in certain brain chemicals
thought to play a key role in
Huntington's disease. Functional MRI studies are also helping
investigators understand how
Huntington's disease kills neurons in different regions of the brain.
Imaging technologies allow investigators to view changes in the volume
and structures of the brain and to pinpoint when these changes occur in
Huntington's disease. Scientists know that in brains affected by
Huntington's
disease, the basal ganglia, cortex, and ventricles all show atrophy or
other alterations.
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