May 10, 2012 Researchers at the Medical Research Council (MRC) Toxicology Unit at the University of Leicester have identified a major pathway leading to brain cell death in mice with neurodegenerative disease. The team was able to block the pathway, preventing brain cell death and increasing survival in the mice.
In human neurodegenerative diseases, including Alzheimer's, Parkinson's and prion diseases, proteins "mis-fold" in a variety of different ways resulting in the build up of mis-shapen proteins. These form the plaques found in Alzheimer's and the Lewy bodies found in Parkinson's disease.
The researchers studied mice with neurodegeneration caused by prion disease. These mouse models currently provide the best animal representation of human neurodegenerative disorders, where it is known that the build up of mis-shapen proteins is linked with brain cell death.
They found that the build up of mis-folded proteins in the brains of these mice activates a natural defense 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 mis-shapen protein keeps the switch turned 'off'. This is the trigger point leading to brain cell death, as those key proteins essential for nerve cell survival are not made.
By injecting a protein that blocks the 'off' switch of the pathway, the scientists were able to restore protein production, independently of the build up of mis-shapen proteins,and halt the neurodegeneration. The brain cells were protected, protein levels and synaptic transmission (the way in which brain cells signal to each other) were restored and the mice lived longer, even though only a very small part of their brain had been treated.
Mis-shapen proteins in human neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, also over-activate this fundamental pathway controlling protein synthesis in the brains of patients, which represents a common target underlying these different clinical conditions. The scientists' results suggest that treatments focused on this pathway could be protective in a range of neurodegenerative disease in which mis-shapen proteins are building up and causing neurons to die.
Professor Giovanna Mallucci, who led the team, said, "What's exciting is the emergence of a common mechanism of brain cell death, across a range of different neurodegenerative disorders, activated by the different mis-folded proteins in each disease. The fact that, in mice with prion disease, we were able to manipulate this mechanism and protect the brain cells means we may have a way forward in how we treat other disorders. Instead of targeting individual mis-folded proteins in different neurodegenerative diseases, we may be able to target the shared pathways and rescue brain cell degeneration irrespective of the underlying disease."
Professor Hugh Perry, chair of the MRC's Neuroscience and Mental Health Board, said, "Neurodegenerative diseases such as Alzheimer's and Parkinson's are debilitating and largely untreatable conditions. Alzheimer's disease and related disorders affect over seven million people in Europe, and this figure is expected to double every 20 years as the population ages across Europe. The MRC believes that research such as this, which looks at the fundamental mechanisms of these devastating diseases, is absolutely vital. Understanding the mechanism that leads to neuronal dysfunction prior to neuronal loss is a critical step in finding ways to arrest disease progression."
The research was funded by the MRC.
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- Julie A. Moreno, Helois Radford, Diego Peretti, Joern R. Steinert, Nicholas Verity, Maria Guerra Martin, Mark Halliday, Jason Morgan, David Dinsdale, Catherine A. Ortori, David A. Barrett, Pavel Tsaytler, Anne Bertolotti, Anne E. Willis, Martin Bushell, Giovanna R. Mallucci. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature, 2012; DOI: 10.1038/nature11058
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