LONDON ¿ An entirely new strategy for treating Huntington¿s disease is likely to evolve following fresh insights into how this inherited neurological disease develops. An international team of researchers has shown that the huntingtin protein that is mutated in Huntington¿s disease regulates the production of a factor that is crucial for the survival of specific brain cells.
Elena Cattaneo, associate professor in the department of pharmacological sciences at the University of Milan in Italy, told BioWorld International: ¿I believe that we have a big chance of getting a cure for Huntington¿s disease because we now know exactly why the disease develops, and we understand the mechanisms by which the mutant gene causes Huntington¿s disease.¿
It would now be possible to screen for drugs that would compensate for the presence of the abnormal gene, she said.
Cattaneo and her colleagues report their findings in a paper published online by Science at the Sciencexpress web site (www.sciencexpress.org) titled ¿Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington¿s Disease.¿
Huntington¿s disease is a devastating illness that affects about one in 10,000 people, although in some parts of the world, such as Venezuela, the incidence is much higher at seven per 1,000. About three to four people in every 10,000 worldwide are at risk because they are the offspring of affected individuals, but only half of them will develop the disease.
The gene that in its mutant form is responsible for Huntington¿s disease was identified in 1993. It encodes a protein called huntingtin. Wild-type huntingtin, which is present in healthy people, has a region containing a stretch of repeated nucleotide triplets, but no more than about 35. If the number of triplet repeats is greater, then Huntington¿s disease will develop. The greater the length of the repeated region, the earlier the onset of the disease.
As a result of the mutation, the huntingtin produced has a region containing many glutamine residues. For reasons that were previously unknown, mutant huntingtin causes neurons in the striatum of the brain to die. People with Huntington¿s disease start to show symptoms at a mean age of 35 years, declining progressively over a period of 15 to 20 years before dying. The movement disorders that are normally present at the onset of the disease are followed by dementia. No effective drug therapy is currently available.
Cattaneo explained that Huntington¿s disease has always been considered a disease in which there is a toxic gain of function in the mutant protein. Mutant huntingtin appears to aggregate in cells, which cannot get rid of it. Furthermore, it activates a cascade of enzymes known to be involved in apoptosis (programmed cell death). Hitherto, therefore, development of drugs has been aimed at blocking these effects.
Cattaneo, working with colleagues in Milan and collaborating with teams in Canada, the U.S. and Sweden, decided to examine the problem from a different perspective. ¿We came to the conclusion that if Mother Nature had developed the gene that encodes huntingtin, then it has to have some function. We thought that the mutation must also interfere with the normal function of the protein,¿ she said. ¿If this turned out to be true, then a therapeutical approach could be directed at restoring this normal function, in addition to combating the toxic gain of function of the mutant protein.¿
Studies carried out by the team and reported in the paper showed that normal huntingtin has a crucial role in supporting certain neurons in the striatum of the brain. ¿We found that huntingtin was neuroprotective because it stimulates the production of a neurotrophin called BDNF,¿ Cattaneo said.
BDNF, or brain-derived neurotrophic factor, is made in the cortex of the brain and transported along nerve cells to the striatum. The group showed that, in transgenic mice expressing mutant huntingtin, there was significantly less BDNF present in both the cortex and striatum of the brain than in transgenic mice that overexpressed wild-type huntingtin.
Other experiments demonstrated that, in mice, wild-type huntingtin boosts transcription of the gene that encodes BDNF. Similarly, transcription of the gene for BDNF was absent from transgenic mice expressing mutant huntingtin.
Tests on biopsies from the brains of people with Huntington¿s disease supported these findings. These samples contained less BDNF than expected, and less BDNF messenger RNA than expected, indicating that transcription of the BDNF gene was, similarly, below normal.
¿These results mean that we have in our hands the molecular target of huntingtin action, which we know is at the level of the BDNF promoter. This means that we can screen for drugs that act at the level of that promoter, exactly as huntingtin is doing,¿ Cattaneo told BioWorld International. ¿I hope that as a result we will be able to identify drugs that mimic the normal function of huntingtin, by increasing BDNF production. An alternative strategy will be to deliver BDNF to the striatal neurons of patients with Huntington¿s disease ¿ either the protein itself or the gene, using gene therapy.¿
As well as pursuing these leads, she expects to carry out further research to gain a better understanding of how huntingtin interacts with the promoter of the BDNF gene.