Closing the door on toxic proteins – new clues in understanding a genetic form of MND

The defects in the C9orf72 gene are known to cause motor neurone disease, but researchers don’t understand why. Defective copies of this gene are passed down in some families affected by the rare, inherited form of MND. This week MND Association grantees Drs Guillaume Hautbergue, Lydia Castelli and colleagues, based at the Sheffield Institute of Translational Neuroscience have published their research study providing some important clues about the toxicity of C9orf72. Their research is published in the prestigious journal Nature Communications. Continue reading

Could a Diabetes drug be useful in treating MND?

Today we announce a new collaboration for a preclinical research study on the diabetes drug liraglutide, in the hope that positive results will lead to a clinical trial in MND. Here’s a little more about the rationale behind the study.

The idea that drugs licensed for one disease may have some use in another completely different disease is not new, but it has gained much more attention in recent years. Researchers are developing a new understanding of disease processes, leading to new ‘drug repurposing’ opportunities, with the additional potential to reduce the time and cost of drug development.

Significant advances in genetics and molecular biology in recent years have greatly increased our understanding of the pivotal, carefully balanced cellular processes that usually keep motor neurons healthy but, when disrupted, can cause a cascade of degeneration leading ultimately to their death. Continue reading

How faulty proteins disrupt waste recycling and disposal inside nerve cells

Researchers from the Sheffield Institute for Translational Neuroscience (SITraN) at the University of Sheffield have uncovered a new function of the C9orf72 protein. A paper on their work has recently been published in the EMBO Journal.

A change or mutation to the C9orf72 gene is linked to about 40% of cases of inherited MND. We also know that changes to this gene also occur in a type of dementia called frontotemporal dementia (FTD). However, the reasons behind this link have so far been unclear.

One of the main research routes towards explaining the link between the C9orf72 gene and MND is to work out the normal function of this gene. By studying the protein the gene produces, researchers can see how alterations to this protein and the processes it is involved with result in nerve cell damage in MND. Continue reading

Can zebrafish help us to learn more about MND?

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. Continue reading

Correcting the early damage seen in MND

Previous research in humans and zebrafish has shown that before symptoms arise in MND, early changes occur in the interneurones. This type of nerve cell provide a link between the upper and lower motor neurones in the brain and spinal cord.

The job of one type of interneurone (called inhibitory interneurones) is to apply the brakes on motor neurones. They work just like brakes on a bike stop the wheels from moving.

The interneurones control when chemical signals/messages (or action potentials) can be passed along the nerve cell. In MND these brakes are less effective (so to use the bike analogy, the brakes might be rusty or not connected properly).

Interneurones are being studied in more detail in a project led by Dr Jonathan McDearmid (University of Leicester), in collaboration with Dr Tennore Ramesh and Prof Dame Pamela Shaw (Sheffield Institute for Translational Neuroscience) (our reference: 835-791). Continue reading

Developing models to test new treatments for MND

Developing disease models is important for furthering our understanding of MND and allows researchers to screen potential new drugs for a beneficial effect. Moving a promising ‘nearly drug’ from the lab to being tested in people is known as ‘translational research’.

Dr Richard Mead

Dr Richard Mead

Dr Richard Mead was awarded the Kenneth Snowman/MND Association Lectureship in Translational Neuroscience in May 2014. The Lectureship is part funded by the MND Association (our reference 983-797).

We have recently received a progress report from Dr Mead. Its clear that his background and experience in this area – including several years working in the pharmaceutical industry – has helped him to rapidly develop a portfolio of projects and collaborations with academic and industry partners. Continue reading

Evaluating a new neck support for people living with MND

We know that neck weakness can be a difficult symptom to manage in people with MND, and that the current offering of neck collars and supports do not always suit everyone. In order to come up with a solution to this, we are funding Dr Chris McDermott from the Sheffield Institute for Translational Neuroscience (SITraN) to develop a new type of neck support for people with MND (our reference: 928-794).

5 b (3)Designers, health professionals and engineers, along with people with MND, have developed a new support called the Sheffield Support Snood. The Snood is an adaptable neck collar, which can be modified to offer support where the wearer requires it most.

The Snood was initially tested in 26 people living with MND in 2014. The current stage of the project, called the Heads Up project, will evaluate the Snood in around 150 people. This will contribute towards providing the necessary wider consumer testing of the Snood, which in turn will help when looking for a commercial partner to take on the manufacture of this product. Continue reading

Understanding more about how the cell’s batteries are affected in MND

PhD student Emma Smith has recently started the second year of her MND Association-funded research project at the Sheffield Institute for Translational Neuroscience (SiTRAN) in Sheffield (our project reference: 870-792). With her supervisors Dr Kurt De Vos and Dr Andrew Grierson she is investigating the role of mitochondria in C9orf72-related MND.

basic cell illustration - E Coulthard

Mitochondria (the brown and orange kidney bean shaped structures shown above) provide the cell with energy. Illustration by Emma Coulthard

Mitochondria are the cell’s batteries, providing them with energy. Earlier research has linked damage to mitochondria as a contributor to why motor neurones die in MND. Based on preliminary evidence, the team are aiming to find how the C9orf72 protein causes damage to the mitochondria, where it happens and what might be done to prevent it. Continue reading

Janine Kirby: My 20 years in MND research

Janine Kirby is a Non-Clinical Reader in Neurogenetics and is celebrating 20 years in motor neurone disease (MND) research this month. Here she tells us more about how she got into the field, her current projects, what it’s like to work at Sheffield Institute for Translational Neuroscience (SITraN) and to meet families affected by MND.

Dr Janine Kirby

Dr Janine Kirby

How and why did you get into MND research?

Having completed my PhD at University College London, I wanted to apply my knowledge of genetics to medical research. I subsequently joined the MND Research Group at the University of Newcastle-upon-Tyne, headed by Prof Pamela Shaw, looking at the frequency of genetic changes in the SOD1 gene in MND patients from the North East of England.

Since then, firstly at Newcastle and then at the University of Sheffield, I have provided genetic input to the research strategy of investigating the molecular basis of this complex genetic disorder. I am now a Reader in Neurogenetics at SITraN working not only on the genetics of MND but also using a method termed transcriptomics (basically which genes are being switched on or off, and by how much) to discover biomarkers for the disease and to understand why the motor neurones are dying.

20 years later I’m still here because it’s incredibly challenging and interesting research, with the opportunity to work with great colleagues and collaborators across the world. Continue reading

Respiratory support: the big debate on Symposium day 2

Different ways to support breathing were the main focus of the second clinical session on day two of the Symposium. Researchers from two MND Association funded studies presented their work looking at diaphragm pacing and also the withdrawal of ventilation support.

Lungs - Symp session pictureDiaphragm pacing

The NeuRx diaphragm pacing system (DPS) is a device developed to aid breathing by stimulating the large muscle that helps you to breathe – the diaphragm.

In 2011, the Food and Drug Agency (FDA) in the USA approved NeurRx DPS as a treatment for respiratory failure in motor neurone disease (MND). The treatment was not required to go through the series of clinical trials that is needed for a new drug. The FDA approved it on the basis of one small study because at the time the probable benefit to health outweighed the risk of using it.

Due to this lack of clinical evidence, this prompted further research in the USA and Europe to test its effectiveness on symptom management and survival. Continue reading