Wednesday, October 12, 2011

Nature's sleeping pill can be used to treat Huntington's

Melatonin is best known for it's actions in the sleep-wake cycle: it's circadian production cycle makes us sleepy in the evening, whereafter the protein is broken down during the night, so that we may wake up in the morning. Surprisingly, researchers have found that melatonin can also play a role in Huntington's disease, a rare hereditary disorder that causes loss of control over muscles, and in a later stage loss of cognitive functions, eventually leading to death. There are virtually no drugs available to treat Huntington's, highlighting the importance of this discovery. Sadly, melatonin is no wonder drug. It only delays the onset of the disease and eases the symptoms.
Scientists injected mice with melatonin, and found that the onset of the disease got delayed by 19 percent. In addition, the progress of the disease was slowed down, resulting in an 18 percent longer life span. Because Huntington's disease is hereditary, prospective patients can be screened. This makes treatment before onset of the disease possible.

Melatonin's mechanism of action in Huntington's is located in the mitochondrium of the cell. This is a cellular compartment that is used as the cell's power plant: it is responsible for creating energy. In addition, the mitochondrium plays a role in controlled cell death, a process that is called apoptosis. Certain factors released from the cellular energy factory trigger a cascade that make cells kill themselves. Apoptosis is a key process in Huntington's, as neurons in the brain are killed by abnormal activation of apoptotic signaling pathways. The loss of brain cells causes several functions of the brain to stop working. It starts with neurons that control muscles, but it progresses throughout the brain, eventually causing cognitive dysfunctions in patients. Onset of damaged neurons usually presents itself in a brain area called the striatum, after which the disease may progress to other areas. The striatum is involved with planning and modulating movement, but also has several cognitive functions.
The striatum, in purple.
Huntington's is caused by a mutation in a gene called Huntingtin, which is expressed in all cells. You need both your copies of this gene to be mutated before getting the disease. This requires both parents to have at least one dysfunctional Huntingtin gene, as both parents pass on one gene copy to their offspring. The highest concentrations of the corresponding Huntingtin protein can be found in the brain and testes. Why a mutated Huntingtin gene causes the disease is not fully understood, but it is known that the Huntingtin protein can act as an anti-apoptotic agent. Loss of its functionality might cause unusual high apoptosis in brain cells. It is also hypothesized that mutated Huntingtin causes damage to mitochondria, and leads to cellular intoxication.

Patients with Huntington's have a life expectancy of about 20 years after the first visible symptoms. Loss of control over muscles, however, cause patients in end-stage Huntington's to require full time medical care. The disease is on par with amyotrophic lateral sclerosis (ALS), which is also a neurodegenerative disease that causes loss of control over muscles. Eventually, loss of respiratory muscles will cause death. Huntington's and ALS have a great impact on the patient and his or her surroundings: the diseases can not be cured, and its progressive loss of motor functions renders the patients unable to do anything over time.

The role of melatonin was discovered long ago, with its production centre located in the pineal gland in the brain. It functions as part of the daily cycle, and makes us feel sleepy. This method of action caused melatonin to be used as a drug to counter insomnia. It is likely that this will be one of the problems when treating human Huntington's patients with melatonin: they will be sleepy all the time. Nevertheless, finding a drug that counters the dreadful symptoms of this disease is promising. Perhaps scientists find a way to synthesize derivatives of melatonin, that do function in the mitochondria, but don't make us sleepy. After their experiments, the researchers noted that they will continue to experiment with different drugs, that act on different cellular pathways, which hopefully eventually creates a cocktail of drugs suitable to treat Huntington's.

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