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.Read More »

Identifying the genetic causes of MND in specific populations

Dr Russell McLaughlin from Trinity College Dublin is one of our Junior Non-Clinical Fellows.

Our Non-Clinical Fellowships were awarded for the first time last year. They aim to retain and develop early and mid-career MND researchers conducting biomedical research. These fellowships are funded for up to four years. We are currently funding two junior and two senior fellowships.

In this three-year research fellowship, which began in January, Dr McLaughlin is studying the more subtle genetic causes of MND (our reference: 957-799).

Why is genetic research important in MND?

We know that for approximately 5-10% of people living with MND, the cause of the disease is primarily due to a mistake within the genes. We also know that very subtle genetic factors, together with environmental and lifestyle factors contribute to why the majority of people develop the disease.

It is likely that these subtle genes are quite rare, and that is why we have not found them so far. As part of his research, Dr McLaughlin is hoping to identify the rarer gene variants that may be linked to MND.Read More »

Using iPSCs to understand why motor neurones lose their normal function in MND

Researchers can create human motor neurones exhibiting signs of MND in the lab by taking skin cells from a person living with MND and reprogramming them into motor neurones. This is called induced pluripotent stem cell (iPSC) technology and gives an ‘in a dish’ human model of MND. iPSCs are being used by several of the researchers we fund.

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Dr Gareth Miles

Dr Gareth Miles from the University of St Andrews, together with former PhD student Anna-Claire Devlin, has previously found that these ‘in a dish’ motor neurones lose their ability to produce an electrical nerve impulse. MND-affected motor neurones at first become overactive, and then subsequently lose their ability to produce the impulses needed to make muscles contract.

In his new project Dr Miles and PhD student Amit Chouhan, alongside Prof Siddharthan Chandran (University of Edinburgh), plans to use iPSCs to investigate why these electrical properties in nerve cells change in MND (our reference: 878-792).

The researchers will look at proteins called ‘ion channels’ that regulate the flow of electrical messages (called an action potential) which travel along the nerve cell towards the muscle.Read More »

Transforming skin cells into nerve cells to understand MND gene mutations

In previous research Prof Kevin Talbot and colleagues at the University of Oxford began to understand more about how the C9orf72 gene defect causes human motor neurones to die. These studies were carried out using an impressive piece of lab technology, called induced pluripotent stem cell (iPSC) technology.

iPSC technology allows skin cells to be reprogrammed into stem cells, which are then directed to develop into motor neurones. Because they originated from people with MND, the newly created motor neurones will also be affected by the disease. Researchers can grow and study these cells in a dish in the laboratory.Read More »

Defining disease progression in MND from MRI ‘snapshots’

Although conventional brain magnetic resonance imaging (MRI) scans are often normal in people with MND, more sophisticated MRI techniques have shown changes in the structure of their brains as the disease progresses. A limitation of even the most recent MRI techniques is that they can only provide a snapshot of the brain at a single moment in the course of the illness.

Only a description of how these MRI changes evolve over time as the disease advances will tell us how the nerve cell damage due to MND is evolving, area by area, in relation to an individual’s symptoms. This could be obtained by collecting several MRI scans from the same person over time, but the nature of MND makes it challenging to get scans showing the course of disease over several years.

We are funding a three year PhD studentship that aims to use a new imaging method to define the progression of MND (our reference: 859-792). The researcher team, involving Profs Mara Cercignani and Nigel Leigh from the University of Sussex, will use MRI scans that have already been obtained from people with MND and healthy controls.Read More »

Using a new imaging technique to shed light on changes to nerve cells in MND

Magnetic Resonance Imaging (MRI) technology is advancing rapidly as a tool for diagnosing and monitoring disease. In MND, MRI scans are used to understand changes that happen to the brain because of this disease.

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Prof Nigel Leigh

Prof Nigel Leigh from the Brighton and Sussex Medical School (University of Sussex) is carrying out a study looking into changes to motor neurones using a new imaging method (our reference: 824-791).

Neurite Orientation Dispersion and Density Imaging (NODDI) is a type of MRI scan, and can see whether MND is affecting specific parts of motor neurones, called neurites, found within the brain. Neurites are the tiny parts of the nerve cells that branch out from the main body of the nerve cell, and are important in the functioning of the brain.

Prof Leigh and his team hope that the new imaging approach will tell us more about the sequence of events that cause motor neurones die, and how this relates to the symptoms of people with MND.Read More »

Working together towards a world free from MND

During MND Awareness Month we are highlighting some of the research the MND Association funds in our ‘Project a Day’ series. Today, on global ALS/MND awareness day, we wanted to give you a look at the research into motor neurone disease taking place elsewhere.

Thousands of researchers across the globe are working towards a world free from MND. Rather than tell you each of their stories, we have gone to those that fund and facilitate this research, and asked them how their efforts bring us closer to figuring out the causes of MND, and finding treatments for this disease.

“I find huge inspiration in the knowledge that when I finish my work for the day, the MND researchers in Australia are just beginning theirs.” Prof Martin Turner, University of OxfordRead More »

Developing the Biomarkers in Oxford Project

Biomarkers in Oxford (BioMOx) is a research project with the aim of identifying a diagnostic biomarker for MND, which could be used to track the progression of this condition.

What are biomarkers?

The aim is to identify biomarkers, or ‘biological fingerprints’ for MND. This could be through testing blood and spinal fluid (CSF) samples from people with MND, or using MRI scans and other imaging techniques to look at changes in the brain.

By understanding the very earliest changes detected in these samples at the start of MND (the biomarker), it is hoped that they could be used to work towards disease prevention and to develop more targeted therapy for those already affected by MND.

For example, including a biomarker element in future clinical trials will help us learn more about the disease and identify participants most likely to benefit from the drug being tested.

Being able to track the progression of the disease could also help with effective care-planning for people with MND.Read More »

Developing a drug screen using nerve cells from a mouse model of MND

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.

TDP43 location in the cell
Location of TDP-43 protein (shown in red) in healthy nerve cells, and how it moves into different parts of the cell in MND

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 »

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.Read More »