New discovery in motor neurone disease and dementia could pave the way to novel treatments

Active nerve cells

A new discovery by scientists at the University of Sheffield could help slow down the progression of neurodegenerative diseases such as motor neurone disease (MND), dementia and neurological decline associated with ageing.

Researchers have identified that tuning up the activity pathway of the DNA’s natural repair toolkit – which normally helps to restore breakages in our genetic material – could help to prevent the death of nerve cells which trigger neurological diseases.

Leading scientists from the University of Sheffield’s Department of Molecular Biology and Biotechnology (MBB) and its Sheffield Institute of Translational Neuroscience (SITraN) examined the C9orf72 gene which contains six DNA nucleotides – the building blocks of our DNA where all important cellular information is stored.

When this series of nucleotides is expanded and repeated multiple times, neurodegenerative diseases can occur. The expansions of the gene forms genetic material called ‘R-loops’ which make the DNA vulnerable to breakages. They found that accumulation of R-loops and increased DNA breakage in neurons lead to neurodegenerative diseases.

Our cells have their own repair toolkits specially designed to fix breaks in DNA, however, the products of the expansion over-activate a process called autophagy – a process that gets rid of misfolded or “unwanted” proteins.

The new study, jointly directed by Professor Sherif El-Khamisy from the University of Sheffield’s Department of MBB and Professor Mimoun Azzouz from SITraN at the University of Sheffield, published today (17 July 2017) in Nature Neuroscience, shows that the expansion driven over-activation of this process can degrade some of the very precious DNA toolkits, meaning the cells will eventually die.

“We were able to shut down the out-of-control degradation process, which runs down the cell’s ability to fix genomic breaks, using genetic techniques,” said Professor El-Khamisy.

“Even though the DNA was still damaged, the cells were able to cope and did not die. Discovering this new mechanism and its consequence is a significant step towards developing new therapies for motor neurone disease and other neurodegenerative conditions.

“More research needs to be done, but it’s possible that this newly discovered mechanism contributes to the death of nerve cells in people suffering from diseases such as Alzheimer’s, Parkinson’s and during the ageing process.”

Professor El-Khamisy, Wellcome Trust Investigator, added: “I’m really excited, if we modulate this degradation process, we can preserve our DNA repair toolkit and take away the pathology, the cell death.”

The discovery based on work conducted in cellular and mouse models of the disease could pave the way for new therapies for devastating diseases such as MND, which is one of the most common neurodegenerative disorders affecting younger people in the middle of their active life.

MND is a progressive and debilitating condition that causes paralysis of muscles in the body leading to difficulties walking, moving, talking, swallowing, and breathing. The rapid deterioration of muscle movement means life expectancy for patients with the disease is three to five years. There are currently no treatments to tackle the disease.

Professor Azzouz, ERC Advanced Investigator from SITraN at the University of Sheffield, said: “This discovery is addressing one of the major challenges of namely the poor understanding of how neurones die in these MND patients.

“The research paves the way for an exciting horizon to accelerate the pace of therapeutic development for MND. Our aim now is to identify targets that can preserve the DNA toolkits and rescue neurons from degeneration.

“I am delighted that this fruitful collaborative effort led to this exciting discovery. Credit to the fantastic efforts from the team, in particular our PhD student Callum Walker. We are looking forward to continuing this work transforming valuable therapies.”

This study is just one example of life-changing research PhD students at the University of Sheffield get the opportunity to work on in collaboration with leading academics from across the world.

For more information about Post Graduate Research at the University of Sheffield, please visit: https://www.sheffield.ac.uk/postgraduate/research

Additional information

To read the full paper please visit http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.4604.html

For more information about University of Sheffield’s Department of Molecular Biology and Biotechnology please visit: https://www.sheffield.ac.uk/mbb/index

To find out more about Sheffield Institute of Translational Neuroscience please visit: http://sitran.org/

European Research Council
The European Research Council, set up by the European Union in 2007, is the prime European funding organisation for excellent frontier research. Every year, it selects and funds the very best, creative researchers of any nationality and age, to run projects in Europe. The ERC has three core grant schemes: Starting Grants, Consolidator Grants and Advanced Grants. It is part of the ‘Excellent Science’ pillar of the EU’s Horizon 2020 programme. For further information, please visit: https://erc.europa.eu/

Wellcome Trust
Wellcome exists to improve health for everyone by helping great ideas to thrive. We’re a global charitable foundation, both politically and financially independent. We support scientists and researchers, take on big problems, fuel imaginations, and spark debate. For more information please visit: https://wellcome.ac.uk/

The University of Sheffield
With almost 27,000 of the brightest students from over 140 countries, learning alongside over 1,200 of the best academics from across the globe, the University of Sheffield is one of the world’s leading universities.
A member of the UK’s prestigious Russell Group of leading research-led institutions, Sheffield offers world-class teaching and research excellence across a wide range of disciplines.
Unified by the power of discovery and understanding, staff and students at the university are committed to finding new ways to transform the world we live in.
Sheffield is the only university to feature in The Sunday Times 100 Best Not-For-Profit Organisations to Work For 2017 and was voted number one university in the UK for Student Satisfaction by Times Higher Education in 2014. In the last decade it has won four Queen’s Anniversary Prizes in recognition of the outstanding contribution to the United Kingdom’s intellectual, economic, cultural and social life.
Sheffield has six Nobel Prize winners among former staff and students and its alumni go on to hold positions of great responsibility and influence all over the world, making significant contributions in their chosen fields.
Global research partners and clients include Boeing, Rolls-Royce, Unilever, AstraZeneca, Glaxo SmithKline, Siemens and Airbus, as well as many UK and overseas government agencies and charitable foundations.

Source: https://www.sheffield.ac.uk/news/nr/new-discovery-in-motor-neurone-disease-and-dementia-1.716976

What is motor neurone disease, what are the causes and early symptoms of ALS and how is it treated?
MND Lucy: 'I hope I don't lose my weird-ass laugh'
'A small piece of strength' stolen from motor neurone disease sufferer every day
Mice with ALS-like Disease Function Better and Live Longer When Protein Receptor’s Activity Is Reduced
Living with Motor Neurone Disease: The symptoms and signs of MND
'I was given a death sentence of 1000 days' - Mum on her devastating Motor Neuron Disease (MND) diagnosis
Report reveals £12k a year cost of living with motor neurone disease
Corrie star Dan Brocklebank: “Motor Neurone Disease is cruel and evil.”
Motor neurone disease: The hidden cost of the debilitating degenerative condition
Doddie Weir diagnosed with motor neurone disease
Motor neurone disease onset delayed by AI-discovered drug
Share This

Be the first to comment

Leave a Reply

Your email address will not be published.


*