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Molecular Genetics
For 10 years, scientists focused on a segment of chromosome 4 and, in 1993, finally isolated the HD 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 HD gene is the first step on the road to a cure.

Finding the HD 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 HD 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 HD, 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 HD to investigators involved in the search for the gene and was an important component in the identification of HD markers.

For several years, NINDS-supported investigators involved in the search for the HD gene made yearly visits to the largest known kindred with HD—14,000 individuals—who live on Lake Maracaibo in Venezuela. The continuing trips enable scientists to study inheritance patterns of several interrelated families.

The HD Gene and Its Product
Although scientists know that certain brain cells die in HD, 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 HD, 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 HD gene cause harm? The HD 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 HD. 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 HD 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 HD
Although the precise cause of cell death in HD 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 HD. 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 HD studies are aimed at understanding losses of nerve cells and receptors in HD. 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 HD affects different subsets of neurons to varying degrees. The hallmark of HD, 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 HD.

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 HD, dendrites grow out of control. New, incomplete branches form and other branches become contorted. In advanced, severe stages of HD, 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 HD 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.