Stuck in FUS – the story of arginines, MND and FTD

In recent news, a number of press releases highlighted a paper published in the journal Cell, in which scientists, under the leadership of the University of Toronto’s Professor Peter St George-Hyslop, and in collaboration with University of Cambridge, described the process of how the FUS protein leads to the development of motor neurone disease (MND) and frontotemporal dementia (FTD).

MND and FTD – what is the connection?

We know that there is a link between MND and FTD, which in most part is caused by a mutation in the C9ORF72 gene, causing familial MND in around 35% cases and FTD in 25% of cases. Mistakes in the gene disrupt normal processes leading to toxic accumulation of TDP-43 protein in the neurons, and their subsequent death. There is however another protein toxic to neurons which results in the development of MND and FTD – the one that makes it slightly easier for us science writers to come up with witty titles: FUS (see one of our previous articles ‘What’s the FUS all about’).Read More »

Mice and Marbles: A CRISPR Model of Motor Neurone Disease

In a study published in Nature Neuroscience this week, a collaboration led by Dr. Jemeen Sreedharan and colleagues from King’s College London, the Babraham Institute and the University of Cambridge have published a new mouse model of Motor Neurone Disease (MND).

The study takes advantage of cutting edge gene editing technology called CRISPR/CAS9 to generate a mouse model of the human disease that accurately mimics a genetic component found in some people affected by MND. The researchers used the gene editing technology to precisely change (mutate) the gene that the body uses to produce the protein TDP-43, a very important player in the MND story implicated in almost all cases of MND.Read More »

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.

Read More »

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 »

Research on the best practical support for people with cognitive change

We know that some people with MND will be affected by cognitive change and a small proportion of these will develop frontotemporal dementia (FTD). The symptoms of cognitive change include changes in planning and decision making.

To help support people with MND who have these symptoms, and their families and carers, we need to firstly identify or confirm these signs are present and then to find ways to help manage them.

The Edinburgh Cognitive and Behavioural ALS Screen (known as ECAS) has been widely adopted as a good method of detecting symptoms of cognitive change. ECAS is a series of tests that are quick to do in the clinic and are specific to MND.Read More »

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.Read More »

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.Read More »

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.Read More »

Are there differences between FTD alone and FTD-MND?

The last of our FTD awareness week blog posts is focussing on a healthcare project looking into FTD (frontotemporal dementia) and FTD-MND (FTD when combined with MND). The project began last year and is being part-funded by us.

Jennie Adams
Jennie Adams

Professor Julie Snowden and PhD student Jennie Adams at the Cerebral Function Unit in Salford (University of Manchester) are looking into the behavioural and cognitive aspects of FTD and FTD-MND.

They are aiming to work out if there are any differences in thinking or behaviour between people who have MND-FTD and those who have FTD on its own.

For example this could be looking to see if people with FTD-MND tend to show more difficulties with language, but not have many changes relating to behaviour. Or if people with ‘pure’ FTD show more difficulties with appropriate behaviour in public, compared to organisation and planning skills.Read More »

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.Read More »