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% of people with the disease 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’).

Specifically, this gene mutation is found in about 4% of people with familial MND and around 1% with sporadic MND. The corrupted FUS gene leads to mistakes in the way FUS protein completes its main role; that is, helping to transport RNA and essential cargos along the cell (especially to the axon and dendrites – projections of the cell body). The FUS protein then gets trapped in the neuron where it forms aggregates. Interestingly, while in FTD this incorrect functioning of the FUS protein is still observed, it hasn’t yet been shown that this is due to a mutation in the FUS gene. (Read more about MND, FTD and FUS in a paper by Nolan et al. (2016).)

So what is the news?

All of the above information is a pretty established knowledge by now. So what did the new paper show? The main purpose of the study was to investigate the exact process by which the FUS protein creates clumps in the neurons and how this could potentially be prevented.

The FUS protein is able to undergo reversible state change, a so called ‘phase transition’– this allows switching from a dispersed liquid form to a droplet-like state or gel-like aggregates (also called phase separation – as the liquid separates into compartments) to accommodate to its surroundings.  This property is required for FUS to form temporary structures that take up, transport, and then release important cargos that control the efficient function and survival of synapses at the distant connecting end of neurons, the synapse.

In healthy cells, FUS can easily switch between the three states to fulfil its role to transport RNA in the solid form and release it as it turns into liquid. In neurodegenerative diseases, and specifically MND and FTD, the FUS protein can get stuck in the solid form, trapping the RNAs and form toxic aggregations within the cell. Understanding how this ‘reversible phase transition’ works is crucial to understand the disease and highlight potential therapeutic targets.

Phase transition
Three states of the FUS protein: dispersed, droplets, and gel-like.

The researchers attributed the fault to an improper ‘methylation’ of the FUS protein. One of the properties of the FUS protein is that, in order to function properly, it attaches a chemical structure called the ‘methyl group’ to one of its amino acids – arginine (remember that proteins are composed of a number of amino acids that are dependent on the sequence of chemical bases in DNA). In normally-functioning FUS, the arginine amino acids making up the protein are heavily methylated.

In FTD however, the FUS protein is ‘hypomethylated’ (hypo = less than the norm) which leads to toxic accumulation of FUS in neurons. What is more, hypomethylation of only less than 5% of the FUS protein can result in triggering of the irreversible gel-like state. It has therefore been suggested that fluctuations in arginine methylation might be responsible for controlling the ability of FUS to be able to undergo reversible state change. So what can we do with these findings?

Using a number of experiments, the liquid/solid state of FUS was manipulated by using varying levels of salts. This led to the observation that reducing salt levels results in less dispersed state and increased phase separation (i.e. formation of droplets). The researchers could then observe the circumstances under which FUS will stay in the dispersed form even in the lowest salt levels. And indeed, when the affected arginine was replaced with other amino acids, or when other amino acids within FUS were reshuffled, the phase separation process was not observed (and the FUS protein stayed in the liquid form).

Next, the team investigated this using frog neurons to clearly visualise nerve axons and their endings, which is where ‘the real action’ occurs (i.e. where the electrical signal is transmitted from one neuron to another). The group mutated the FUS protein in the neurons by either reducing the number of building blocks of the protein that could be methylated, or by introducing changes in order to increase aggregation of the FUS protein.

The team demonstrated that a protein called Transportin1 acts as chaperone – assistant and guide – that prevents the FUS protein from aggregating in the neuronal nucleus. By tagging the transportin with a fluorescent marker, they could see its movement with the FUS protein attached along the axon. This showed the importance of Transportin1 to maintain the ability of FUS to transition normally and to potentially ‘rescue’ some of the aggregation of the FUS protein.

This important work shows that the protein Transportin1 and the methylation of arginine, building block of the FUS protein, play a vital role in preventing aggregation of the protein in MND and FTD. By identifying the specific changes that may stop the formation of the toxic aggregates in FUS, the race is now on to use enzymes that can modulate the amino acids in FUS and have a protective role for the protein (keep it from turning into the irreversible solid state).

How does this fall into the ‘finding a cure’ puzzle?

Year on year we see an increase in the number of significant findings that lead us closer to solving the MND cause/cure puzzle faster. The study described above is a great example of this; while it is not THE solution we are all hoping for, it provides a clearer picture of one segment of the whole MND jigsaw. Techniques that were used to find out how FUS behaves, how it can be manipulated and what can prevent its toxic aggregation, can be translated into studying different variations of MND, also caused by toxic aggregation of a protein (such as TDP-43 or SOD1).


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 »

Fathoming MND

This article was written by our Senior Clinical Fellow Prof Martin Turner, a Consultant Neurologist at John Radcliffe Hospital, Oxford.

“Will it affect my children?” This is one of the questions most commonly asked by people diagnosed with MND. The 20th century answer was a simple “no”, or at least “very unlikely”. With recent scientific advances, however, doctors must give a more complicated answer. At the same time, these advances are cause of excitement about the greater understanding of MND and new hope for treatments for all cases.Read More »


Yesterday, we were delighted to unveil a new research collaboration that we believe will greatly improve the quality and pace of MND research – not only in understanding the cellular processes that cause motor neurons to degenerate, but also in helping with drug discovery and development.

The Amyotrophic Lateral Sclerosis Reproducible Antibody Platform (ALS RAP) isn’t anything to do with the musical genre. It isn’t really a research project either. Instead, it’s focusing on the importance of providing the scientific community with ‘gold standard’ tools for their research.

This new collaboration involves a group of universities that make up the Structural Genomics Consortium, working with industry partners alongside three MND research organisations: The ALS Association, ALS Canada and ourselves.Read More »

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 »

Standing on the shoulders of… Dorothy Hodgkin

On the way to work last Wednesday, a story on BBC Radio 4 – ‘Today programme’ suddenly grabbed my attention: “February will mark the 100th anniversary of women having the right to vote!”

Curiosity sparked, I turned up the radio: “BBC Radio 4 are holding an online vote for the most influential British women of the past century. Each day in the run up to the anniversary we’ll be shortlisting and celebrating a candidate for the award”.

Last Wednesday’s nominee was Dorothy Hodgkin, the only British woman to ever win a Nobel Prize in the sciences. Dorothy won her award in 1964 for developing a technique that enables the complex structure of proteins to be deciphered – this is known as protein crystallography. Dorothy used this technique to work out the structure of insulin, vitamin B12 and penicillin.

Funnily enough, I had recently been discussing this technique with my colleague Jessica. I told her the news story when I got to work and we decided we’d share with you how, thanks to Dorothy’s brilliant work, protein crystallography is currently helping researchers funded by the MND Association to find out more about MND.Read More »

Tackling weight loss in MND – from ProGas to PostGas

Swallowing problems are an incredibly common cause of malnutrition and weight loss in MND patients. To add to this, weight loss in MND is associated with shorter survival. This means managing swallowing problems effectively is crucial to ensuring people living with MND can have the best possible quality of life.

Managing swallowing problems using gastrostomy

Swallowing problems in MND are often managed by placing a feeding tube directly into a patient’s stomach – this is known as a gastrostomy. The feeding tube can either be placed into the stomach via the mouth, or directly from outside the body.

An MND Association-funded study that concluded in 2015 provided much needed evidence on the best method and timing for gastrostomy. This study, known as ProGas, was led by Professor Chris McDermott at the Sheffield Institute for Translational Neuroscience (SITraN).Read More »

It’s not just about the neurones

Long before the latest wave of cellular and molecular biology advances started to give us new information on what was going on at the cellular level in MND, some doctors had observed that if the disease started in one particular part of the body, it would be neighbouring parts that became affected next.  This suggested that the disease usually starts in a single part of the brain or spinal cord before spreading further, like ripples in a pond.

How this happens is not well understood. It is likely that there are a number of processes going on, but they can broadly be divided into two theories. One of these is that damaged proteins can leak out of sick neurons and ‘infect’ their neighbours – a subject we have discussed at previous international Symposia.Read More »

Catch up on Symposium…focus on causes and treatments

Following on from our previous catch-up blog on clinical management talks presented at the Symposium, here is a continuation that looks at talks focusing on treatment therapies and causes of MND.

RNA Binding & Transport

RNA is the lesser-known ‘cousin’ of DNA – it contains copies of genetic instructions sent out from the nucleus – the ‘control hub’ of every cell. This RNA is carried out of the nucleus by lots of different proteins, including the RNA-binding proteins TDP-43 and FUS, which act as ‘couriers’ dropping off their RNA at the right part of the cell and then returning to the nucleus for the next package.

These binding proteins both play an important role in motor neurone health. In motor neurones affected by MND, the TDP-43 and FUS seem unable to make their way back to the nucleus so they form clumps in other parts of the neurone. How and why this happens is not really understood and several presentations on the first day of the Symposium provided insight into what might be going wrong.  Dr Brian Dickie, Director of Research Development at the MND Association, summarises these presentations in his blog Libraries, Doormen and Harry Potter. You can also hear Brian talk about RNA proteins on the Symposium website.Read More »

Catch up on Symposium…focus on ‘clinical management’

From abstracts to posters, pushpins to ribbons, it takes a whole year to get to this day – no, not Christmas, but the 28th International Symposium on ALS/MND. In this and the following ‘catch-up’ blog we will summarise what went on at the Symposium and where you can find out more information. To begin with, you can read about what goes into organising the biggest meeting of its kind on our blog:  It’s that time of year again … #alssymp.

Because of the diversity of the talks presented at the Symposium, we categorised them into five key themes that follow the timeline ‘from bench to bedside’; biomedical research, diagnosis and prognosis, causes of MND, clinical trials and treatments, and improving wellbeing and quality of life. You can read more about each of these themes on our Symposium LIVE webpages.Read More »