Prof Vladimir Buchman (Cardiff University)’s research was selected as one of the best research studies, as decided by the journal editors, published in the Journal of Biological Chemistry in 2013. He is building on this research in his Association-funded project, which began on 1 April 2014.
The background to FUS:
In 2009 an international team of scientists, including researchers funded by the Association, identified the FUS gene as a cause of approximately 4% of inherited MND cases (5-10% of total MND cases).
The FUS protein formed by this gene is usually found in the nucleus or ‘control centre of the cell’. A change in the structure and/ or function of the FUS protein leads to motor neurone damage and the development of MND. This change causes the FUS protein to ‘wander’ outside of the cell nucleus and form protein ‘clumps’ within the cell.
These protein clumps, as well as being found in 4% of inherited MND cases, are found in many cases of MND and the related disease, frontotemporal dementia. At present it is still not clear how this happens and how these clumps of FUS protein cause MND.
What the researchers have found so far
In the Open Access research paper, which was highlighted as one of the best research studies in the Journal of Biological Chemistry in 2013, Prof Buchman and Dr Tatyana Shelkovnikova identified that the clumping of the FUS protein within motor neurones resulted in MND.
The research also showed that the symptoms seen in mice where similar to what are seen in people living with MND – highlighting the importance of animal models in the study of MND.
Two types of FUS
At the MND Association, we fund research that builds on recognised success, and Prof Buchman’s research is a great example of this. In their Association funded project, which began earlier this month, Prof Buchman and Dr Shelkovnikova aim to build on their FUS research and advance our understanding of MND.
They will study in detail how MND develops, and the role of FUS, in a mouse model of the disease. Dr Shelkovnikova also aims to create another mouse model that produces a different FUS protein that is unable to bind to RNA (the cell’s copy of our genetic material – DNA).
An important function of FUS is that it regulates the genetic information from DNA in the nucleus to where it can be used to make proteins (where it is copied into RNA). Prof Buchman proposes that when FUS is unable to bind to RNA it leads to the formation of protein clumps within motor neurones, leading to the symptoms of MND.
Why the researchers need two different mice models
The reason why the researchers need two different mouse models of MND, each with a slightly different mutated FUS protein, is because people living with MND do not have the same FUS protein mutation – they have slightly different mutations that may affect the protein in different ways.
By studying these two mouse models, with slightly different FUS proteins the researchers can find out more about the FUS protein, and ultimately using the two mouse models to test potential drugs. Commenting on their Association-funded research project, Prof Buchman said: “We believe that our proposed studies of FUS will pave the way to more targeted drug design and treatments that will stop the progression of the disease in people living with MND.”
Testing potential treatments
By understanding more about the FUS protein in MND Dr Shelkovnikova hopes to identify new potential targets for therapeutic drugs; using both mouse models to test the research group’s recently created new class of neuroprotective chemicals. These are drugs that the researchers believe could potentially be used to combat protein clumps in neurodegenerative diseases like MND.
By testing these drugs in animal models, the researchers can tell whether these treatments stand a good chance of working in humans. Our external reviewers highlighted that this study “Clearly addresses very relevant questions on MND research in vivo. It is critical to understand how mutations in FUS lead to toxicity, and the role of RNA binding on toxicity. Moreover, it is critical to provide the community with novel mouse models of MND.”