In a study published in Nature Neuroscience this week, a collaboration led by Dr. Jemeen Sreedharan and colleagues from King’s College London, the Babraham Institute and the University of Cambridge have published a new mouse model of Motor Neurone Disease (MND).
The study takes advantage of cutting edge gene editing technology called CRISPR/CAS9 to generate a mouse model of the human disease that accurately mimics a genetic component found in some people affected by MND. The researchers used the gene editing technology to precisely change (mutate) the gene that the body uses to produce the protein TDP-43, a very important player in the MND story implicated in almost all cases of MND.Read More »
In April 2016, Dr Jackie Mitchell gave a talk at the Regional Conference in Gatwick to explain the aims of her three year MND Association funded research project. We have now received her second year report. In this blog we explain a little bit more about what she’s been doing. She has already made some good progress.
A little bit of background
One known genetic cause of MND is a defect in the TARDBP gene, which makes the protein TDP-43, that can be found in the nucleus of a healthy cell. The nucleus is the part of the cell that contains all our DNA. Healthy cells also have two major ‘waste disposal systems’ which break down and remove unwanted proteins from cells. More information on the role of TDP-43 in MND can be found on our blog.Read More »
I firmly believe that the quality of research is only as good as the researcher doing it, which is why the MND Association places a lot of emphasis on providing opportunities to attract, train and retain the brightest and best investigators in the UK and Ireland to develop their careers in MND research. These range from our ‘entry level’ PhD Studentships through to our successful Clinical Fellowships (funded jointly with MRC) and our more recent Non-Clinical Fellowship programme, offering opportunities to outstanding young researchers at a variety of career stages.
The MND Association are funding Prof Kevin Talbot, Dr Ruxandra Dafinca (née Mutihac) and colleagues at the University of Oxford, who areinvestigating the link between the C9orf72 and TDP-43 genes in MND. We wrote about this research earlier in the year. As we’ve recently received their first year progress report we wanted to give you an update on what they’ve achieved.Read More »
Induced pluripotent stem cell (iPSC) technology has enabled researchers to create and study living human motor neurones in the lab, derived originally from patient skin cells.
This project (our reference 80-970-797) is a collaboration between the labs of Professors Chris Shaw and Jack Price at King’s College in London and Siddharthan Chandran in Edinburgh. It aims to use the already collected white blood cell samples within the UK MND DNA Bank to create a larger number of new iPSC models of MND. Ultimately creating an MND iPSC cell bank, these models will enable researchers to better understand the disease and screen potential new drugs.Read More »
In a previous research project funded by the MND Association, Prof Kevin Talbot and colleagues from the University of Oxford developed a new TDP-43 mouse model of MND. Compared to other mouse models of MND, this one accurately reflects the symptoms of the disease and levels of the TDP-43 protein as seen in humans.
This model of MND also shows how the TDP-43 protein becomes displaced from the nucleus (command centre of the cell) out into the cell cytoplasm, which makes up the cell body. Once TDP-43 has moved to the cytoplasm it is very difficult to shift, as it forms protein aggregates or clumps. It is thought that these clumps contribute to motor neurone cell death.
Prof Talbot’s latest project, together with researcher Dr David Gordon, is using cultured nerve cells from this new mouse model to screen a large library of drugs (our project reference: 831-791).
In the next two years, they will create an automated computerised imaging system that can detect the TDP-43 protein within the nerve cells (and see if it has moved out of the nucleus). With this imaging software the researchers aim to screen thousands of drug compounds in a short space of time, including some which have been approved for other illnesses. A ‘good’ drug will make TDP-43 stay in the correct location within the nerve cell’s nucleus.Read More »
We know that damage to C9orf72 (both the gene and the protein it makes) is a crucial step in why some people get MND and why some people get frontotemporal dementia. There are three possible reasons why C9orf72 is toxic. 1) the way the gene is damaged alters how it normally works. 2) the formation of clumps of RNA – a by-product of the damage and not normally seen in cells, and 3) the formation of very short, new and unwanted proteins called ‘dipeptide repeats’ or ‘DPRs’, again these are not normally seen..
There’s evidence of all three types of toxicity within the motor neurone, but we don’t know how they work together or if one is more toxic than another. We also know that the protein TDP-43 forms clumps in motor neurones affected by the C9orf72 gene.Read More »
A team at the Sheffield Institute for Translational Neuroscience are creating a zebrafish model to study the C9orf72 gene mutation in MND, and work out its role in the brain and spinal cord (our reference 864-792).
Zebrafish are a good way of modelling what happens in human MND. We know that many of the genes linked to causing MND in humans are also found in zebrafish. For example, changes to a gene called SOD-1 in humans are linked to about 20% of all cases of inherited MND, and when you genetically change the same gene in zebrafish they develop symptoms similar to MND.
A faulty or changed C9orf72 gene is associated with about 40% of all cases of the inherited form of MND. This change (or mutation) is also found in people with a form of dementia called frontotemporal dementia (FTD). FTD can alter abilities in decision-making and behaviour.Read More »
Dr Frank Hirth is one of the world’s leading fruit fly MND researchers. Based at the Institute of Psychiatry, Psychology and Neuroscience at King’s College London, he has been working on an Association-funded project developing a C9orf72 fruit fly model of MND. Here we mark the end of this project, and report on what the researchers have achieved.
In September 2011, an international collaboration, co-funded by the Association, had discovered a genetic mistake within the C9orf72 gene that was found to cause almost 40% of cases of inherited MND. Read More »
Researchers identify that loss of nerve signalling may be an early sign of MND
Published in Nature Communications on 12 January 2015, Association-funded PhD student Anna-Claire Devlin, based at the University of St Andrews, has identified that loss of nerve signalling may be an early sign of MND.
Under the leadership of Dr Gareth Miles and Prof Siddharthan Chandran (University of Edinburgh), Anna-Claire measured the nerve impulses in stem cell derived human motor neurones and identified that the ability to send a nerve impulse is impaired during the early stages of the disease. Read More »