Work Experience with the Research Development team

Kiera portrait.JPGMy name is Kiera Belson and I have just completed three days of work experience at the Motor Neurone Disease (MND) Association for an award called the Youth STEMM Award. This consists of doing different activities and experiences linked to the different STEMM sectors: Science, Technology, Engineering, Maths and Medicine. The work I have done at the MND Association has been linked to the Science and Medicine sectors.

During the time I spent here, I have learnt things about MND as well as researching a technique called induced Pluripotent Stem Cell (iPSC) technology (see below), which has been my main task over the three days. I have also learnt about the Research Development team and what they do at the Association, including management of the ‘UK MND Collections’, a resource of biological samples from people with MND, and the different categories within this: the DNA bank, the cell lines collection and the epidemiology collection.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.

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.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 »

MND stem cell study identifies TDP-43 astrocytes as not toxic to motor neurones

Funded by the MND Association, international researchers have used stem cell technology to learn more about the relationship between motor neurones and their support cells.

These findings highlight the potential of stem cell technology as a tool to create new human ‘in a dish’ cellular models of disease to learn more about the causes of MND.

Prof Siddharthan Chandran and Sir Prof Ian Wilmut at University of Edinburgh looking at a stem cell image

The research group included MND Association funded researchers Prof Siddharthan Chandran and Sir Prof Ian Wilmut from University of Edinburgh, Prof Chris Shaw from King’s College London and Prof Tom Maniatis from Columbia University in America.

This important finding was published in the scientific journal PNAS on 11 February 2013. This new finding follows on from previous work published by this research group in 2012 where they demonstrated the proof of principle of creating human motor neurones with MND in a dish.

Why we need an astrocyte model of MND

Astrocytes, so called because of their star-like appearance, normally act as neurone support cells to nourish and protect motor neurones. They act with motor neurones to ensure that they can continue to function.

From previous studies, we know that when these cells begin to dysfunction, they can become toxic to motor neurones to contribute to MND. Finding out why astrocytes can cause motor neurones to degenerate is an issue of ongoing debate – we recently gave an update on this from the International Symposium.

Being able to grow human astrocytes in a laboratory dish is of importance to be able to learn more about the relationship between astrocytes and motor neurones in MND.

Creating human astrocytes in a dish

Using cutting-edge stem cell technology, the research group reprogrammed skin cells into astrocytes in a laboratory dish. The skin cells were donated by people with MND who have a family history of the disease caused by known mistakes in a gene called TDP-43.

Led by Prof Chandran and colleagues, the research group aimed to identify whether these cells would develop the ‘hallmarks’ of MND in a laboratory dish.

By studying the characteristics of these human astrocytes with faults in the TDP-43 gene, the research group identified that they shared the same qualities as cells affected by MND. The astrocytes had increased levels of TDP-43 found in areas where it isn’t usually found – outside of the control centre of the cell. They also found that the astrocytes didn’t survive as long as astrocytes created from skin cells of people that didn’t have MND.

This means that the human astrocytes created by Prof Chandran and colleagues using stem cell technology develop MND-like characteristics. This new model can be used to study how motor neurones develop the disease in a system that is directly relevant to people living with MND.

Answering whether faulty astrocytes affect healthy motor neurones

The next question that this research group wanted to answer was whether these faulty astrocytes had an effect on healthy motor neurones.

By growing faulty TDP-43 astrocytes with healthy motor neurones, the research group identified that the survival of motor neurones was not adversely affected.

This was surprising as other research groups have shown that when astrocytes have faults in the SOD1 gene (which cause one in five cases of MND with a family history) that motor neurones are compromised, even if the motor neurones were originally healthy.

TDP-43 is found within tangled lumps in over 90% of cases of MND (irrespective of whether it was caused by an inherited genetic mistake). However, when MND is caused by SOD1, TDP-43 is not found in these tangled lumps. This important difference could be leading to the key difference in whether astrocytes become toxic to contribute to causing MND.

These findings will of course need to be verified by an independent research group to determine that they are valid, but the results suggests that SOD1 and TDP-43 could be causing havoc in motor neurones in slightly different ways, both avenues leading to MND.

Our Director of Research Development, Dr Brian Dickie comments: “From a therapeutic perspective this is important because it means that specific treatments targeted at astrocytes may only be relevant and effective, in specific subsets of patients who will have to be carefully selected for drug trials.”

References:

Our news release on this finding.

March 2012 finding: Association-funded stem cell study achieves milestone

Serio A et al. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. PNAS 2013