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Novel Therapeutic Target for the Treatment of Huntington?s Disease

ScienceDaily (July 23, 2010) ? An article published in The Journal of Biological Chemistry presents a novel pharmacological target that, in combination with a neurotrophic factor, could be used to improve the survival of striatal neurons, the principal nerve cells affected by the neurodegeneration observed in Huntington's disease.

The study was conducted by the researchers Silvia Gin?s, a lecturer in the University of Barcelona; and Paola Paoletti, a doctoral student and Jordi Alberch professor with the Department of Cell Biology, Immunology and Neurosciences in the Faculty of Medicine in the UB.

Huntington's chorea is a progressive neurodegenerative disease caused by a genetic mutation of the gene encoding for the protein Huntingtin. The disease principally affects the basal ganglia, which regulate motor control and other important functions. One of the most widely studied potential therapeutic targets for the treatment of Huntington's disease is the brain-derived neurotrophic factor (BDNF), essential in the survival of striatal neurons and severely depleted in Huntington's sufferers.

The researchers used an in vitro cell model to study whether the cells that express the mutated Huntingtin respond to administration of BDNF. "We concluded that treatment with BDNF is an effective therapeutic strategy for this disease, but that combined treatments are probably needed to modulate different aspects of the pathology," explains the UB researcher Silvia Gin?s, who is also a researcher for the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and the Networked Biomedical Research Centre for Neurodegenerative Diseases (CIBERNED).

In order to act, the neurotrophic factor BDNF must bind to the catalytic receptor TrkB, levels of which are also reduced in Huntington's disease. The receptor is the key to activating signalling of the three pathways involved in the survival of the striatal neurons. The researchers reproduced the conditions of the disease and induced oxidative stress, which alters the metabolism of the nerve cells and affects their DNA. They found that under oxidative stress, two of the pathways function correctly when BDNF is administered but the third (MAPK/ERK1/2) does not.

To improve the treatment response, the team used the activator PMA, a phorbol ester of which scientists are trying to find a suitable human analogue. The next step in the research, as Silvia Gin?s explains, is to find "modulators of the third pathway (MAPK/ERK1/2) as a possible final treatment and possibly even to develop a strategy for modulating the receptor itself to increase the efficiency of the response."

Although the genetic mutation affects the whole body to some degree its principal impact is on the brain, where it causes severe degeneration of the striatal neurons as well as a lesser degree of generation in the cerebral cortex and the hippocampus. Huntington's patients cannot coordinate their movements and are affected by uncontrollable contractions known as chorea, making it difficult for them to lead a normal life.

Researchers are also studying the molecular mechanisms contributing to the cognitive defects observed in the initial stages of the disease, which are known to cause alterations of executive memory, thus affecting the sufferer's ability to complete or organize simple everyday tasks.

Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Universidad de Barcelona, via AlphaGalileo.


Journal Reference:
Silvia Gines, Paola Paoletti and Jordi Alberch. Impaired TrkB-mediated ERK1/2 Activation in Huntington Disease Knock-in Striatal Cells Involves Reduced p52/p46 Shc Expression. Journal of Biological Chemistry, 2010;

DOI: 10.1074/jbc.M109.08420

I think this is very interesting, Bob, thanks for posting it. I'm wondering if the best strategy to make treatment with BDNF more effective is to come up with a modifier of the third pathway as the authors suggest or if it is to reduce oxidative stress.

hmmm, that was interesting

I hate to say this, but when I read some of this stuff, I think, boy that's going to take a long time from theory to treatment.

So Marsha, what do you think? Eric is right. How long will this take?

They don't have a drug to activate the pathway yet so it could be years before they develop one and then it has to be tested for safety and efficacy in mice and maybe it will need to be tweaked. We've been waiting four years now for a Caspase Six inhibitor, for example.

Still, I think this is a worthwhile study because it suggests to me that treatments to boost BDNF will need to be combined with antioxidant treatments.

Sally, it depends on how you look at it. If I look at it for my children personally... anything after today is too long. Same for anyone here if I widen out the people I care about personally whom I know. The wait feels like forever in those terms. There is always going to be someone who needs better treatment of HD, and in those terms... when it comes, it will be needed for them as much as for people now and the people who came before us. So the wait sometimes gets to me, and I have to use perspective about it. If it comes in 5 years, some people will still just miss the boat, or 50 years. But everyone from that point on have better. Thousands and thousands.

I am almost feeling like the word "cure" and the question of "how long for the cure?" should almost be expunged for our thinking. No matter how well intentioned anyone who tries to guess how long, they are batting 1000 on being wrong. Some day someone who says ten years will happen to be right, but not because they knew it when they said it. I am trying to concentrate on the here and now, getting everyone now as much as possible and in the best position to work for all the future things as quickly as possible. To me this a reasonable response to the cure/treatment questions. The fewer people involved in any level of HD the longer it will take. I am pretty certain of that. There should be enough people to go around but there aren't yet.