Novel therapeutic target for the treatment of Huntington’s disease

The study was conducted by the researchers Silvia Ginés, 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 Ginés, 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 Ginés 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.