New ALS review article available

ammar2.jpgLast week, The New England Journal of Medicine (NEJM) published a review article by Professors Ammar Al-Chalabi and Robert Brown, in which they looked at the up to date evidence on the incidence of ALS, pathological mechanisms of the disease, as well as genetics and therapeutic strategies.

We would very much like to thank the NEJM who kindly allowed us to share full text of this article on our website – this is now available to view here.

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

Exploring the interaction between TDP-43 and RNA

In light of the upcoming Biomedical Research Advisory Panel meeting happening on Friday 7 April that will discuss which new research projects the MND Association will fund, we are pleased to report on the progress of one of our already-funded researchers. In their three year project, funded by the MND Association, Prof Annalisa Pastore (King’s College London) and Prof Gian Tartaglia (University Pompeu Fabra, Barcelona) are investigating the process by which TDP-43 binds to RNA. Below is a summary of the progress they made during their first year.

Background to the project

Alumni Board Meeting 2008

Annalisa Pastore, King’s College London

One of the causes of amyotrophic lateral sclerosis (ALS), the most common type of motor neurone disease (MND), is related to faulty functioning of the TDP-43 protein, a component that is naturally present in all of our cells. In healthy cells, TDP-43 resides in the centre of a cell (the nucleus) where it attaches to RNA and supports correct gene expression – that is, it helps to extract information carried by a gene to form proteins, the main building blocks of our bodies.

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

Spreading the seeds of an idea: MND disease pathology

With motor neurone disease (MND), the muscle weakness almost always starts in a single part of the body, with the weakness then spreading to other muscles in an orderly fashion. Neurologists are usually quite good at predicting which muscles will be affected next, slightly less so at predicting when this will happen.

The physical changes on the outside will be reflecting events occurring in the ‘closed box’ that is the brain and spinal cord. The latest imaging techniques are starting to give us more of a picture of what’s happening in the central nervous system as the disease progresses, but further technological advances will still need to be made. The clearest picture still comes from the study of generously donated and incredibly valuable post-mortem tissue.

The second day of the Symposium saw researchers present in the Clinical-Pathological Correlates of Disease Progression session, focussing on how to understand disease progression, the role of prions in neurodegenerative diseases and the relationship between MND and frontotemporal dementia. Continue reading

Hunting for clues about the genetic causes of FTD and MND

Yesterday we published an introductory blog on frontotemporal dementia (FTD) and described how it is sometimes found in combination with MND.

Today we are looking at a biomedical project on FTD and MND that we are funding.

The project

Dr Olaf Ansorge and Professor Kevin Talbot of Oxford University are leading a biomedical project aimed at identifying cell changes in the brain tissues of people who had MND, FTD, or developed both conditions (FTD-MND).

The aim of their research project is to identify which nerve cells within the brain are most likely to be affected by faulty proteins known to contribute to both FTD and MND. Knowing which brain cells are affected, and by which proteins, will help explain the genetic differences between the two conditions. Continue reading

Do retroviruses contribute to the common, sporadic form of MND?

New research from scientists at the American National Institute of Neurological Disorders and Stroke in Bethesda suggest that they might. In a research paper published in Science Translational Medicine yesterday, Li, Nath and colleagues proposed that sporadic MND may be linked to an endogenous retrovirus called ‘HERV-K’. So they conducted a series of experiments to investigate their ideas further.

What are endogenous retroviruses?
These are viruses that are our body’s equivalent of fossil – a left over from our evolution many thousands of years ago. Everyone has them but they are normally in an inactive state.

They are a bit like a family heirloom, lets say a vase. You might walk past the vase every day without really noticing it until one day the cat knocks it off and it smashes onto the floor in front of you.

What did the researchers do?
First, they compared brain tissue of 10 people who died from the sporadic form of MND to brain tissue of 10 people who died from Alzheimer’s Disease. They found proteins made by the virus in MND brain tissue but not in Alzheimer’s Disease brain tissue. Next, studying one of these proteins (called ‘env’) in more detail, they found it was toxic to motor neurones.

Li and colleagues then took a step back and asked ‘what triggered HERV-K to become active in the first place?’. (In other words, going back to my analogy, what caused the vase to fall on to the floor?). They found that the trigger was activation by a protein called ‘TDP-43’ – and this protein is already linked MND.

So what does this really mean?
In a comment article giving a wider perspective on the research study, Professors Bob Brown and MND Association grantee Ammar Al-Chalabi concluded:

The exciting observations of Li, Nath and colleagues will provoke further follow up studies that will illuminate the interplay between the biology of endogenous retroviruses and seemingly impenetrable neurodegenerative disorders like ALS”.

So while this study in itself might not give us the answer, its an exciting step forward in understanding the most common form of MND, that other researchers around the world will build on.

Li et al Human endogenous retrovirus-K contributes to motor neurone disease Sci Transl Med 7 307ra153 (2015)

Brown and Al-Chalabi Endogeneous retroviruses in ALS: a reawakening? Sci Transl Med 7 307fs40 (2015)

‘Dormant viruses may cause MND when awoken’ article in The Guardian

Oxidation Resistance 1 – tackling oxidative stress

MND Association-funded researchers, Prof Dame Kay Davies and Dr Peter Oliver, both based at the University of Oxford, have identified the oxidation resistance 1 (OXR1) gene as a neuroprotective factor in MND.

Published in the journal Brain on 9 March 2015, Prof Davies has shown through their recent research in mice that OXR1 may serve a new target for future drug development.

We’re funding Matthew Williamson’s PhD studentship to follow up this exciting research. Find out more about this and the other research projects funded by the Association in our newly updated Research we fund information sheet. Continue reading

Breaking the Human Genome Code

Dr Johnathan Cooper-KnockProfessor Winston Hide gave his inaugural lecture on 17 March, during Brain Awareness week, entitled ‘breaking the human genome code – opening Pandora’s box’, which you can watch in full at the end of this blog post.

Professor Hide recently joined the University of Sheffield, and MND Association/ Medical Research Council (MRC) Lady Edith Wolfson Clinical Research Fellow, Dr Johnathan Cooper-Knock has written a blog below about Professor Hide’s research and how they are working together towards a world free from MND: Continue reading

Making antisense of RNA editing

helena chaytow 2Association-funded PhD student, Helena Chaytow (Royal Holloway, University of London), is using DNA to develop a targeted treatment for MND. Now entering her final year, we report on what she’s achieved so far and her future plans.

The background

Helena’s research is looking at the chemical messenger ‘glutamate’. Glutamate is released by motor neurones in order to stimulate a nerve impulse from one motor neurone to the other, which is how the instruction to move our muscles travels from our brain to our limbs.

In order to pass the message on, glutamate needs to bind to the second nerve cell, and it does this by acting like a ‘lock and key’. Continue reading