Abnormal protein makes Huntington's disease patients sick

An aggregating protein causes many of the symptoms of Huntington's disease, an incurable and frequently fatal brain disorder. Mosaic winner Ahmad Aziz discovered that the abnormal protein also aggregates in the hypothalamus, the part of the brain that regulates the autonomic nervous system and the endocrine system.

Ahmad Aziz investigated the severity and causes of a number of less well-known symptoms of Huntington's disease: weight loss, sleep disturbances and a poorly functioning autonomic nervous system. He established that many patients suffer from weight loss and sleeping problems. Abnormalities in the hypothalamus appear to account for some of these symptoms.

The hypothalamus was an obvious suspect for Aziz, as it regulates the autonomic nervous system and the endocrine system. Aziz established that certain nerve cells are lost in a part of the hypothalamus. In this part as well as in other parts of the hypothalamus abnormal protein aggregates were found. These hypothalamic nerve cells play an important role in the maintenance of body weight and a normal sleeping pattern.

Many of the patients investigated by Aziz get to sleep too late and wake up later in the morning than healthy people. Moreover, it appeared that the further the sleep rhythm is displaced, the more depressive the patients are. These patients also suffer from more cognitive abnormalities. The disruption of the sleeping rhythm could partly be due to a shift in the rhythm of the 'sleeping hormone' melatonin. That rhythm is regulated by the biological clock in the hypothalamus. Many Alzheimer's patients also have an abnormal sleep/wake rhythm. This can partially be corrected by light therapy and the administration of melatonin. Huntington patients might also benefit from such an approach.

Although the mutated Huntington's disease gene mainly causes damage in the brain, it is expressed in virtually all tissues, even though it does not cause damage everywhere. However, Aziz demonstrated that weight loss in the initial stages of Huntington's disease is not the consequence of other symptoms, such as hyperactivity, but is directly related to the mutation. This indicates that the cause must partly lie in the peripheral tissues, such as muscle and fat tissue. The defective gene probably causes damage there as well.

Huntington's disease is caused by a mutation in the huntingtin gene. In the mutated gene the DNA sequence C-A-G is repeated too often. Aziz's research reveals that weight loss and the number of CAG repeats are directly correlated: the greater the number of repeats, the greater the loss of weight.

The number of CAG repeats in the normal huntingtin gene can also influence the symptoms of the disease. This is because each person carries two copies of the huntingtin gene. In a normal gene there are 35 or less CAG repeats. Huntington patients have one normal gene and one defective gene with 36 or more repeats. Aziz discovered that the number of CAG repeats in both the normal gene and the defective gene is important for the rate at which the disease progresses. However, the effect of the normal gene is small and is mainly important for understanding how the disease develops and for a correct interpretation of future drug studies. It follows that such studies must take into account the differences in the number of CAG repeats in both genes.