Life of an MND researcher – part 2: PhD edition

Each year, the MND Association dedicates the month of June to raising MND awareness. This year, we focus on the eyes – in most people with MND the only part of their body they can still move and the only way left for them to communicate. Alongside the Association-wide campaign, the Research Development team selected six most-enquired about topics, which we will address through six dedicated blogs.

In our previous article we introduced four MND researchers who gave us an insight what a typical day in the life of a researcher looks like and what carrying out a research study actually involves. In this continuation article, you will get the chance to look into the lives of four PhD students, who give us an overview of their projects and their usual daily duties. Continue reading

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.

GBMiles

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. Continue reading

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. Continue reading

Developing ultrasound imaging as a potential non-invasive diagnostic tool for MND

When diagnosing MND, it is important to look at the activity and impact of the motor neurones themselves – is the electrical message being carried down the nerve properly, and is it reaching the end of the nerve in the muscle? Malfunctions in the electrical activity at the muscle end of the nerve cell result in the muscle twitching that many people with MND experience.

One of the tests used to diagnose MND is an electromyography or EMG test. It involves putting needles into a muscle to measure electrical activity. It can be a painful and unpleasant experience, which doctors and patients are only willing to do when necessary.

There is evidence that ultrasound imaging may be able to detect the same malfunctions in the electrical activity of muscle as EMG, by looking at the way the muscle behaves when electrical activity occurs. Ultrasound images produce the typical grey scale images, for example pictures from baby scans, and can be used to provide images of any muscles in the body. Continue reading

Investigating C9orf72 and TDP-43 proteins in a fruitfly model of MND

Background to C9orf72 toxicity

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. 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

Protecting motor neurones against oxidative stress in MND

During the early stages of MND it is proposed that motor neurones are more susceptible to an imbalance of oxygen within the cells, known as oxidative stress. Prof Dame Kay Davies, at the University of Oxford, has previously shown that increasing the levels of the gene Oxr1 can protect motor neurones from death caused by oxidative stress and delay MND in mice. You can read about this work here. Continue reading

Is frontotemporal dementia different when found with MND?

Some people with MND develop an increasingly recognised form of dementia, known as frontotemporal dementia  or FTD (for more information visit http://www.ftdtalk.org/). The main symptoms of FTD include alterations in decision making, behaviour and difficulty with language.

The relationship between MND and FTD is not well understood. Prof Julie Snowden and PhD student Jennie Saxon at the Cerebral Function Unit in Salford (University of Manchester) are aiming to establish whether MND combined with FTD is subtly different to when FTD is found on its own (our grant reference: 872-792).

People diagnosed with FTD-MND, with FTD alone, and those with no form of dementia will perform a series of short cognitive tasks. These will test things including a person’s ability to recognise emotions, draw inferences about the thoughts of others, their ability to concentrate, organise actions and understand language. 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

Using fruit flies to understand a genetic cause of MND

Mistakes in a gene known as ALS5, or spatacsin, cause a rare form of inherited MND that develops at a much earlier age than most other forms of the disease. Under supervision from Dr Cahir O’Kane, MND Association funded PhD student Alex Patto has been using fruit flies to understand how mistakes in spatacsin cause MND (our grant reference 861-792).

Prior to this research, which is based at the Department of Genetics at the University of Cambridge, nothing was known about how faulty spatacsin leads to motor neurone degeneration. Three and a half year years on, this research has shed light on this important question.

What did they find?

By conducting tests in the fruit flies, Alex has found that the spatacsin protein has a role in cell recycling (also known as autophagy), a process which keeps cells healthy. When the spatacsin protein is faulty it leads to disrupted cell recycling and abnormal levels of another protein called Rab7, which might contribute to MND development. Continue reading