Huntington’s disease (HD) is a neurologic disorder characterized by chorea (uncontrollable body motions) and progressive cognitive decline; symptoms and signs usually begin in the third or fourth decade of life and progress inexorably. There is no cure, and patients typically die within ten to twenty years of symptom onset.
HD is a hereditary disorder caused by an autosomal dominant gene. Both males and females are affected equally, and children of a parent with HD have a 50% chance of acquiring the disorder (if both parents are affected, all of their children will also eventually acquire the disease).
The Molecular Underpinnings of Huntington’s Disease
- For some time it has been known that the chromosomal anomaly responsible for HD causes production of an abnormal protein called huntingtin. This protein is present in all tissues of the body, but it only seems to cause damage to nerve cells.
- The amount of huntingtin that is produced (and stored) in the body’s tissues can increase with successive generations. With time, this can lead to increasingly severe disease within a given family tree. (Merck Manual, 18th Edition. Huntington’s disease. 2006:1881)
Hope for Huntington’s Disease…and Other Brain-Destroying Conditions
- To date, treatment for HD has been supportive only: agitation and chorea can be partially suppressed with antipsychotic medications, but most patients are eventually institutionalized.
- The discovery by Dr. Solomon Snyder's team at Johns Hopkins may be the first step toward developing an effective treatment for HD and other neurodegenerative diseases.
- Using human embryonic cells and brain cells taken from mice, the Johns Hopkins scientists mixed huntingtin with another little-known molecule—one that is only found in certain neurons—called Rhes. This started a chemical reaction that was toxic to the cells; the reaction did not occur when Rhes was mixed with normal proteins, or when huntingtin alone was added to the cells.
- Thus, the combination of Rhes and huntingtin is apparently what starts the toxic chemical reaction (called sumoylation) that leads to the brain damage which is characteristic of HD. (Srinivasa Subramaniam, Katherine M. Sixt, Roxanne Barrow, Solomon H. Snyder. Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity. Science 2009:324(5932):1327 - 1330
Implications for Alzheimer’s Disease
Interestingly, the brains of patients with HD contain microscopic clumps—called aggregates—of huntingtin. In this respect, HD resembles Alzheimer’s disease and other neurodegenerative disorders; many of these conditions are characterized by the presence of aggregates of abnormal proteins.
The Johns Hopkins scientists believe that these protein aggregates result from healthy cells’ attempts to sequester abnormal proteins and prevent them from causing damage. When the chemical reaction between huntingtin and Rhes occurs, healthy cells are unable to “corral” the huntingtin, and the cells are eventually destroyed.
This last finding may help to settle a debate that has raged among scientists for years. While many investigators feel that aggregates are the underlying cause of tissue damage that leads to brain destruction, others feel the aggregates are evidence of the brain’s effort to limit further damage.
Dr. Walter Koroshetz, Deputy Director of NIH’s National Institute of Neurological Disorders and Stroke, remarked that the Johns Hopkins discovery suggests that it is the soluble proteins, rather than the aggregates, that cause the problems.
“The answers in one disease may have implications for another,” noted Koroshetz.
Eventually, effective treatments for conditions like Huntington’s disease and Alzheimer’s dementia may stem from this research. Meanwhile, scientists at Johns Hopkins and other institutions are quickly mobilizing to expand on this initial breakthrough.
