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Medical Research Council scientists discover compound that arrests neurodegeneration in mice

Wednesday 9 October 2013

Researchers at 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 prevented neurodegeneration in the mice.

 

The team had found previously (Nature) 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 mechanism 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 today 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 compound, which had originally been developed by GlaxoSmithKline for a different purpose, was able to enter the brain from the bloodstream and halt the disease, throughout the whole brain. However, this compound, despite protecting the brain, also produced weight loss in the mice and mild diabetes, due to damage to the pancreas.*

 

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.

 

Professor Giovanna Mallucci, who led the team, said, “Our previous study predicted that this pathway could be a target for treatment to protect brain cells in neurodegenerative disease.  So we administered a compound that blocks it to mice with prion disease. We were extremely excited when we saw the treatment stop the disease in its tracks and protect brain cells, restoring some normal behaviours and preventing memory loss in the mice.

“We’re still a long way from a usable drug for humans – this compound had serious side effects. But the fact that we have established that this pathway can be manipulated to protect against brain cell loss first with genetic tools and now with a compound, means that developing drug treatments targeting this pathway for prion and other neurodegenerative diseases is now a real possibility.”

 

Professor Hugh Perry, chair of the MRC’s Neuroscience and Mental Health Board, said, “Misshapen proteins in prion diseases and other human neurodegenerative disorders, such as Alzheimer’s and Parkinson’s, also over-activate this fundamental pathway controlling protein synthesis in the brains of patients. Despite the toxicity of the compound used, this study indicates that, in mice at least, we now have proof-of-principle of a therapeutic pathway that can be targeted. This might eventually aid the development of drugs to treat people suffering from dementias and other devastating neurodegenerative diseases.”

 

Ends

*It wasn’t possible to study this group of mice at greater length because despite brain protection they lost 20 per cent of their body weight which, under Home Office regulations, means they had to be killed.

 

Notes to editors

 

An oral treatment targeting the unfolded protein response prevents prion neurodegeneration and clinical disease in mice

Julie A. Moreno, Mark Halliday, Colin Molloy, Helois Radford, Nicholas Verity, Jeffrey M. Axten, Catharine A. Ortori, Anne E. Willis, Peter M. Fischer, David A. Barrett and Giovanna R. Mallucci

 

The Medical Research Council has been at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Twenty-nine MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. www.mrc.ac.uk  The MRC Centenary Timeline chronicles 100 years of life-changing discoveries and shows how our research has had a lasting influence on healthcare and wellbeing in the UK and globally, right up to the present day. www.centenary.mrc.ac.uk

The University of Leicester is a leading UK University committed to international excellence through the creation of world changing research and high quality, inspirational teaching. Leicester is the most socially inclusive of Britain's top-20 leading universities.  Times Higher Awards Winner 2007, 2008, 2009, 2010 and 2011.

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