A team of researchers led by Professor Giovanna Mallucci from the Medical Research Council (MRC) Toxicology Unit at the University of Leicester, who last year identified a major pathway leading to brain cell death in mice, have used an orally administered compound to block the pathway and have prevented neurodegeneration in the mice.
The team had previously found that the build up of misfolded proteins in the brains of mice with prion disease over-activates a natural defence mechanism in cells, which switches off the production of new proteins. This would normally switch back ‘on’ again, but in these mice the continued build-up of misshapen protein keeps the switch turned ‘off’. This is the trigger point leading to brain cell death, as the key proteins essential for nerve cell survival stop being made.
Originally, the team injected a protein that blocked the ‘off’ switch of the pathway into a small region of the brain, and by doing this were able to restore protein production, and halt the neurodegeneration. The brain cells were protected, and protein levels and synaptic transmission (the way in which brain cells signal to each other) were restored allowing the mice to live longer. This led the scientists to predict that compounds able to block this pathway would also protect brain cells.
In the new study, published in Science Translational Medicine, the researchers gave by mouth a drug-like compound against the pathway to prion infected mice, hoping to block the off-switch in the same way.
The researchers studied mice with prion disease because these mouse models currently provide the best animal representation of human neurodegenerative disorders in which the build up of misshapen proteins is linked with brain cell death. These include Alzheimer’s and Parkinson’s as well as prion diseases. Another paper in Nature Neuroscience last month highlighted this pathway as a potential therapeutic target in treating Alzheimer’s.
It is believed that the findings may also eventually aid the development of drugs to treat people suffering from dementias and other devastating neurodegenerative diseases.