Is Huntington's Disease Reversible?
BY RICHARD KESSIN, PH.D. ASSOCIATE DEAN FOR GRADUATE AFFAIRS
HUNTINGTONS DISEASE IS A DEVASTATING NEURODEGENERATIVE disorder characterized by progressive motor disturbances, cognitive deterioration, and personality changes. It is inherited as an autosomal dominant. In humans it usually appears at about age 40. For the past eight years we have known the cause of Huntingtons diseasea protein called huntingtin sometimes has a large number of glutamines at one end. When a patient has more than 40 of these repeated amino acids incorporated in their huntingtin, insoluble inclusions in the brain result and these appear to lead to the disease. Although many people have studied this disease, including Columbias own Nancy Wexler, questions remain. Are neurons killed when inclusions form? Why are these inclusions not dealt with by normal cellular protein degradation mechanisms? Is the disease reversible?
In the face of such neuropathology, it might be natural to assume that the effects are irreversible and that even if, by some miracle, the excess huntingtin found in the inclusions could be degraded, the patient would be beyond recuperation. That may be so, but recent experiments by René Hen and his graduate student Ai Yamamoto give us reason to think that irreversible damage should not be assumed.
The human disease is difficult to study so researchers have created a mouse model. In this lengthy, but now standard, procedure, a gene coding for huntingtin (plus extra glutamines) was inserted into a mouse oocyte, which was then re-implanted into a mouse. This manipulation resulted in transgenic mice that overexpressed the defective form of huntingtin. Did the mice develop Huntingtons disease? Yes. The mice are normal at first, but then acquire the staggering gait, loss of activity, and brain neuropathology that occur in human patients. In fact, the huntingtin protein is not needed to produce the diseaseonly 96 repeated glutamines expressed in all tissues of the body are required. But these earlier experiments had a limitation. One could not turn off the huntingtin gene and it was expressed in all parts of the body. Affected mice deteriorated and died.
What Yamamoto and Hen decided to ask was whether the damage observed in the brains of Huntingtons patients and in the mice was irreversible. To do this they fused a huntingtin gene (with extra glutamines) to a promoter that could be regulated. A promoter is a piece of DNA that does not code for a protein but controls the expression of a particular gene. Yamamoto and Hen judiciously chose a promoter that was expressed exclusively in the brain and that could be regulatedturned off and on by regulating the diet of the mice. Give them a normal diet and the gene is expressed, the defective form of huntingtin is made, and, predictably, the mice develop the disease. The promoter turns off when the experimenter adds tetracycline to the diet. The gene is silenced and no new defective huntingtin is made.
By this time, Ai Yamamoto was several years into the process. She had fused the regulated promoter to huntingtin and inserted this piece of engineered DNA into transgenic mice. When the pups were born, there was another waitto see if they developed the disease. Summaries such as this one tend to make experiments sound easy, but this series of experiments could have failed at any step, leaving Ai without a thesis.
Now imagine a small group of affected mice, each sickening with the staggered gate of Huntingtons disease. Half of them are fed tetracycline. They recover over a period of weeksthey cease to stagger and on subsequent neuropathological examination, the inclusions in their brains have disappeared. The untreated controls continue to sicken and die. The results suggest that as long as no new defective huntingtin is made, the brain can recovera constant assault of new protein is necessary to maintain the symptoms. While a complete extrapolation to human brains is unwarranted, Ai and Renes results are the first indication that this devastating disease can be reversed.