A step forward has been taken in understanding the genetic disorder Huntingdon's after the discovery of a protein whose mutation causes it to stop functioning properly and trigger the disease.
Until now, the function of huntingtin, the gene responsible for the disease, had been poorly understood. It is now hoped this novel discovery could, in the long term, lead to new therapeutic techniques for blocking the accelerated death of neurons that characterises the disease.
Whilst the identity of the gene responsible for Huntington's in 1993, there is presently no cure for the disease. Patients can be screened for the mutated gene, but little can be offered in the way of treatment, which at present merely alleviates symptoms.
The study, published on 9 July in the journal Cell, discovered, in its normal state, huntingtin protects neurons against cell death. However, once it is mutated, the reverse occurs, resulting in the rapid death of neurons in the striatum, the brain region where Huntington's disease arises.
The group, from the French CNRS (National Centre for Scientific Research) and INSERM (National Institute for Health and Medical Research) detail the interaction between huntingtin and the HAP1 protein. HAP1 is the first huntingtin interactor identified, and it seems to work alongside proteins involved in vesicle transport.
The current study provides evidence that huntingtin enhances vesicle transport of brain derived neurotrophic factor (BDNF) which is essential for maintaining the type of brain cells that die off in patients with Huntington's.
BDNF transport is weakened by the introduction of mutant huntingtin. The alteration of huntingtin and HAP1 is linked with reduced association of motor proteins with microtubules. The loss of BDNF transport appears to be associated with reduced neurotrophic support and cell toxicity.
An estimated 30,000 patients in the US and 40,000 in Europe suffer from Huntingdon's disease. It is a rare neurological disorder that usually begins between the age of 35 and 50. Like Alzheimer's or Parkinson's, the disease is typified by the abnormal death of certain neurons.
The most prominent indicators of Huntington's are involuntary and jerky movements of the limbs, head and neck. Other symptoms include mental disorders such as anxiety, irritability, depression and intellectual decline leading to dementia. Death typically occurs 15 to 20 years after the onset of the disease, usually due to complications such as pneumonia.
The Institut Marie Curie said in a statement: "Although still at the research stage, this work opens up new investigational pathways in the treatment of Huntington's disease. In the longer term, other diseases, like cancer, in which apoptosis plays a fundamental role, could also benefit from those discoveries."
The latest study follows on the heels of research done at the University of Iowa in the US. Researchers demonstrated for the first time that physical symptoms and neurological damage caused by an inherited neurodegenerative disease that is similar to Huntingdon's disease may be prevented by gene therapy.
The results of the study were significant because they showed the delivery method of the RNAi via a viral vector (a stripped-down virus) could be used to deliver small interfering RNA (siRNA) fragments to critical brain cells of mice with a disorder that mimics the human neurodegenerative disease spinocerebellar ataxia 1 (SCA1).
The siRNA material was designed to bind to and suppress the disease-causing SCA1 gene. It was the first example of targeted gene silencing of a disease gene in the brains of live animals which suggested this approach might eventually be useful for human therapies.
Despite the amount of research activity into Huntingdon's, the relatively small number of sufferers involved means that large pharmaceutical corporations are less interested in producing drugs to deal with the disease. These so-called "orphan" drugs qualify for special grants and fast track regulatory procedures, particularly in the US.
Although there are a small number of sufferers, estimates as to the potential market for Huntingdon's drugs could run to several hundred million euros. Sufferers of Huntingdon are likely to have to take medication regularly over several decades to alleviate the worst symptoms of the disease.
Currently there is no cure for Huntington's disease. Drug treatments are available to help people manage some of their symptoms such as abnormal movements. Antidepressants such as fluoxetine (eg Prozac) can be helpful with depression, and mood stabilisers and antipsychotic drugs can help with some of the emotional disturbances.