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

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. Continue reading

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. 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

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. 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

Cognitive Change and MND

In addition to the muscle weakness and wasting, MND also presents with non-motor symptoms, one of the most common being cognitive change.

Research has already shown that changes can occur to the nerve cells in the frontal and temporal lobe areas of the brain. These are the two areas which are responsible for controlling thinking, reasoning and behaviour.

Frontotemporal dementia, or FTD for short, is a rare form of dementia (cognitive impairment). One sub-type of FTD is sometimes found in people who have MND.

The first ever World FTD Awareness week is being held between 4-11 October.

To help raise awareness we are posting a series of blogs this week looking at FTD and research we are funding into this condition.

What is FTD?brain

The main symptoms of FTD are linked to behavioural and mood changes, such as loss of inhibitions, being unable to empathise with others, or showing repetitive behaviours.

Many people with FTD also have changes to their speech and vocabulary, such as using the wrong word for something – for example calling a sheep a dog, or becoming less articulate in their speech. Some people can also gradually lose their ability to speak.

Thinking can also be affected, with FTD affecting someone’s ability to plan properly and their organisational skills.

FTD is brought about by nerve cells within the frontal and temporal lobes of the brain dying, because the pathways connecting the nerve cells to each other become altered. The chemical messengers that pass on information from one nerve to another can sometimes also be lost.

More information on FTD can be found on the NHS website, FTD Talk website or on the FTD support forum.

There are also two information sheets that the Association produce covering changes to thinking: ‘Will the way I think be affected?‘ and ‘How do I support someone if the way they think is affected?‘.

Healthcare professionals can also access our resources on cognitive change, FTD and MND on the ‘For professionals’ area on our website. Continue reading

Is MND/FTD the same as FTD alone?

brain Association-funded researcher, Prof Julie Snowden from the University of Manchester was invited to present her research on MND and frontotemporal dementia at this year’s 25th International Symposium on ALS/MND. She is asking whether people living with MND and frontotemporal dementia develop a different form of dementia that is different to those with frontotemporal dementia alone.

In 2011, when researchers discovered the C9orf72 inherited-MND gene, it was also linked to the related neurodegenerative disease frontotemporal dementia (find out more about inherited MND here). This increasingly recognised form of dementia has different signs and symptoms to the more common Alzheimer’s disease, but is less understood.

Researchers are now studying these previously separate diseases together. By working collaboratively with dementia researchers, we are beginning to understand this gene and the link between the two diseases. But what precisely is this link? In the past there were distinct disorders? Prof Snowden answered these questions as thinking of MND and FTD as a spectrum.  Continue reading

Postcard from Australia

Emma Devenney at this year's symposium in Milan

Emma Devenney at last year’s symposium in Milan

Dr Emma Devenney is an MND Association and Neuroscience Research Australia funded PhD student investigating the Cerebellum in MND and Frontotemporal Dementia at Neuroscience Research Australia. She is finding out what role it plays in the symptoms of patients with the C9orf72 mutation. Here she blogs about her work from Australia!

Finally after more than 12 months of preparation and anticipation I touched down in Sydney to be greeted by a city in the throes of early summer. Sydney in the summer is the epitome of the Australian dream and it is easy to see how it has enticed many Irish and British immigrants to its shores. The blue skies, beautiful beaches and a lively cultural and social scene are amongst many of the cities attractions and distractions.

Neuroscience Research Australia is in the exuberant Eastern suburbs of Sydney; an area where the British and Irish expatriate communities have integrated well into Australian society and are as reliant on a daily ‘flat white’ as any self-respecting Australian. The research centre is located down the hill from the Prince of Wales hospital in the suburb of Randwick. Continue reading

Chromosome 9 finally reveals its secrets

It’s taken a huge international collaboration, including 3 MND Association-funded scientists, to discover a genetic mistake that appears to cause almost 40% of cases of familial (inherited) MND – that’s nearly twice as many as are caused by mutations in the SOD1 gene and more than three times as many as are caused by TDP-43 and FUS combined. Yet despite the fact that it’s relatively common, the rogue gene proved especially difficult to find.

Digging for genes

Our genetic code is arranged into 23 pairs of subunits called chromosomes. Earlier work had homed in on an area on chromosome 9 that appeared to be significantly associated with both MND and the related neurodegenerative disease frontotemporal dementia (FTD), but nobody could drill down as far as the problem gene itself. As a result, chromosome 9 became something of an ‘archaeological dig site’ for MND researchers, with several groups using cutting edge techniques to try and excavate the elusive causative gene that they knew was lurking somewhere in the short arm of this chromosome. The successful international team, which included almost 60 scientists at 37 institutes, finally discovered the exact location and nature of the aberrant genetic code by looking in the most unlikely of places – in the stretches of DNA that do not actually provide any instructions for building proteins, otherwise known as non-coding DNA.

What did the researchers unearth?

The research team studied DNA samples from a Welsh family affected by inherited MND and FTD that was already known to be associated with chromosome 9, as well as samples from a similar Dutch family and a large number of Finnish inherited and non-inherited MND cases. In among the non-coding DNA in a chromosome 9 gene called C9ORF72, the researchers found a 6-letter genetic ‘word’ which, in healthy individuals, is consecutively repeated up to about 20 times. However, in the Welsh and Dutch families and a large proportion of the Finnish familial cases, the 6-letter word was repeated as many as 250 times. This phenomenon is known as a ‘repeat expansion’. The researchers went on to check for this repeat expansion in familial MND cases from North America, Germany and Italy, and found it cropped up in 38% of them. They even found it in a much smaller proportion of sporadic cases from Finland, suggesting that it could be an important risk factor in at least some people with the  non-inherited form of the disease.

What does the discovery mean for MND research?

Despite the fact that the repeat expansion does not directly affect the instructions for building a protein, there is good reason to believe that it can still lead to significant neuronal damage. At the moment it is not fully understood how this happens, but one possibility is that it leads to the production of excessive and consequently toxic quantities of RNA, the molecule that provides the cell with a more usable copy of DNA. Disruption to RNA processing has already been implicated as a disease mechanism in MND – this is the pathway through which faulty TDP-43 and FUS are thought to exert their effects – so C9ORF72 may provide scientists with another piece of the RNA jigsaw.

The effect of the repeat expansion is clearly open to influence. Among those people with the repeat expansion, some experienced only FTD, others showed only muscle weakness, and some had both MND and FTD.  The reasons for this variation in symptoms will be just one area that scientists will now want to look into. This overlap between MND and FTD is something that researchers are very keen to understand, and the C9ORF72 discovery may be the key to solving this puzzle. They will also want to better understand how the repeat expansion causes damage, and that will include trying to find out what C9ORF72 actually does – at the moment this is unknown. (Maybe it’ll get a more interesting name along the way!) Building on the new finding in this way could help move us closer to an effective treatment.

For now, a more tangible consequence of the discovery could be a genetic test for people already diagnosed with familial MND who want to understand more about the basis of their disease. Such a test will take a little time to develop but should become available in the UK in the next few months. When it does, it will be accessible to genetics labs across the country. Anyone interested should speak to their doctor or specialist nurse.  

Dead heat

Just as archaeologists might question whether a newly discovered artefact is the real thing, so scientists need double-checking when they claim to have made a new discovery. Fortunately, a second team hit upon C9ORF72 at exactly the same time, and their results will be published alongside the work described here, in the journal ‘Neuron’. The race to the ‘Lost Ark’ of chromosome 9 ended in a tie, but has provided the research community with a major piece of the MND puzzle on which to build future discoveries.

Article: Renton A, Majounie E, Waite A et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked amyotrophic lateral sclerosis-frontotemporal dementia. Neuron (2011).

Read our press release on the C9ORF72 story.