New genetic discoveries tell us more about what causes MND – Part 2

Two sets of MND genetic results were published yesterday. One of these results was about the importance of a new gene called NEK1. The second highlighted the role of gene C21orf2 in MND – we wrote an article about this yesterday. Both sets of results were published in the prestigious journal Nature Genetics.

What are the results and what do they tell us?

Researchers found that variations in the NEK1 gene contribute to why people develop the rare, inherited form of MND. Variations in the NEK1 gene were also found to be one of the many factors that tip the balance towards why people with no family history develop MND.

NEK1 has many jobs within motor neurones including helping keeping their shape and keeping the transport system open. Future research will tell us how we can use this new finding to target drugs to stop MND. 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

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. Continue reading

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. 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

Flying towards an understanding of TDP-43

If you looked at the motor neurones of people with MND down the microscope you would see clumps of a protein called TDP-43. Researchers around the world are working to find why these clumps form and how they are linked to MND.

Dr Jemeen Sreedharan has been looking at the effects of TDP-43 in fruit flies. Initially he investigated how TDP-43 caused its effects, later moving on to find ways to reduce or prevent the damage. He spent the first two years of his MRC and MND Association-funded Fellowship (our reference: 943-795) working at the University of Massachusetts, Boston USA returning last autumn to perform the next stages of his research at the Babraham Institute near Cambridge, UK. Continue reading

Finding a connection between the cell’s waste disposal system and MND

Just like when we put out our recycling every week, the cells in our body have their own recycling system too. One of the recycling plants within our motor neurones works by a system called autophagy. In a recently completed research project that the MND Association has funded Dr Rob Layfield and Dr Alice Goode have been looking at how malfunctions in autophagy cause MND (our reference 821-791).

Their research has focussed on how a gene called SQSTM1 and the protein it makes (the protein is known as ‘p62’) is involved in MND. The project has gone well and we have a much better understanding of how cell recycling goes wrong in MND. 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

More clues to the inner workings of the C9orf72 gene

Continuing the ‘gene hunting theme’ on from our last blog post on Project MinE, a recently published study has shed more light on the C9orf72 gene mutation.

The C9orf72 gene mutation is the most common cause of the rare inherited form of MND (about 40% of all people with inherited MND have this mutation). Some people with the sporadic form of MND also have this mutation, and it has been linked to the development of a type of dementia called frontotemporal dementia (FTD).

Figuring out the normal function of C9orf72

A study by Jacqueline O’Rourke and colleagues at Cedars-Sinai Medical Centre in Los Angeles used mice that lacked the equivalent gene to C9orf72.

When this gene was absent, the mice developed normally and their motor nerve cells were unaffected.

From this evidence they discounted one of theories about the C9orf72 mutation – that a change to the gene stops it working entirely and that this affects the health of motor neurons. Continue reading

Looking for MND genes: Project MinE update

Project MinE is an international genetics project that is analysing DNA from people with MND in detail.

For the majority of people with MND, the disease appears ‘sporadically’ for no apparent reason. For a small number of people, approximately 5-10% of those with MND there is an inherited link, in other words the disease runs in their families.

We know a lot about the genes that are damaged in the rare inherited forms of MND. We also know that very subtle genetic factors, together with environmental and lifestyle factors contribute to why the majority of people develop the disease. These subtle genetic factors are very hard to find.

The goal of Project MinE is to find the other genes that cause inherited MND and help us find out more about these subtle genetic risk factors.

mine

Project MinE was born when Dutch entrepreneur Bernard Muller challenged his neurologist to do something with all the DNA samples in his freezer – samples being stored there for future analysis. ‘Why can’t those samples be analysed now?’ was his question. That was two years ago! Continue reading