New gene finding suggests recycling is key to all forms of MND

Researchers from Northwestern University Feinburg School of Medicine in America, have identified that faulty ubiquilin 2 plays an integral role to MND.

Led by eminent researcher Prof Teepu Siddique this research group describes unique mistakes in a gene called UBQLN2, which codes for a protein called ubiquilin 2, in five families with the inherited form of ALS. This research group also found that this protein is found in both the inherited and sporadic form of MND, which suggest that this finding could be key to finding a new treatment for the disease. Their findings were published in the prestigious Journal Nature.

What did the researchers do?

The researchers started by identifying a novel genetic mistake in a gene called UBQLN2 for a family affected by the inherited form of ALS. ALS is the most common form of MND. They went on to duplicate this finding by identifying four more genetic mistakes in the same gene in four other families with inherited ALS. This verified that this finding is not simply a ‘one off’.

By examining post-mortem spinal cord samples from people with ALS within these families, faulty ubiquilin 2 was identified as being involved in forming ‘tangled lumps of proteins’ within their motor neurones. When a researcher looks down a microscope at a motor neurone with the disease this ‘tangled lump’ is a classic sign of MND.

The next question that this research group addressed was whether ubiquilin 2 could also be found in other forms of MND. Remarkably, by studying post-mortem samples of people with the randomly occurring ‘sporadic’ form, inherited form (caused by mistakes in SOD1, TDP-43, FUS or an ‘unknown’ gene) and fronto-temporal dementia – related MND, they identified ubiquilin 2 within the ‘tangled lump’ in all of the samples.

This means that ubiquilin 2 could be the ‘smoking gun’ of MND.

Never before has one single protein or gene been related to all forms of ALS. Until now.

Mistakes in this gene are very rare and as yet, we don’t know how many cases of inherited MND are caused by it. This discovery does not open up the possibility of a new genetic test to identify people who might be at risk from the disease, but it does provide a new and exciting insight into the causes of all forms of MND.

How does ubiquilin 2 cause MND?

Imagine a world where all recycling collectors are on strike. Every Wednesday at 7am you place a box of recycling on your driveway ready to be collected, but it’s still there in the evening. The next week you put out more recycling, and that isn’t collected either. After weeks of putting your recycling outside, you notice that the pile is mounting and still isn’t being collected. This doesn’t bother you too much as you can still step over it, albeit in a slightly slower manner. A few months pass and you can no longer get out of your driveway as it’s covered by recycling. Now you can’t get rid of your rubbish, you can’t get to work and you can’t even leave your house all because of the pile up of recycling. The same thing is happening to everybody all over your town. This is what happens in MND.

One of the pathological hallmarks of MND is a build-up of ‘recycling bins’ of proteins in motor neurones. Normally, these recycling bins are emptied on a regular basis by a process regulated by a family of proteins called ubiquitins – of which ubiquilin 2 is a member. This build up of recycling causes pandemonium in cells, as vital movement of nutrients around the cell cannot easily pass to where they need to get to, causing an additional burden to the motor neurones. Eventually, the motor neurones start to degenerate because of this.

What now?

These results will now need to be verified in more people with MND. However, this study could revolutionise the MND research world and provides evidence that the recycling pathway plays a crucial role in MND. Researchers now need to find out how the recycling pathway is involved with MND which could provide insights into how new treatments could be developed to target the disease.

We’ll be keeping a close eye on ubiquilin 2 in the future!

Read our press release on this news story.

Read the Scotsman article on this story.

Reference: Nature (2011) DOI:doi:10.1038/nature10353

UPDATE: Prof John Mayer from University of Nottingham takes you even further behind the scenes of this news story.

MND Association funded researcher featured on JNNP podcast

At last year’s 21st International Symposium on ALS/MND, we told you about a study which suggested that handedness is linked to the site of onset (Handedness linked to symptom onset – Lessons from a poster presentation). Talking about his research on the Journal of Neurology, Neurosurgery, and Psychiatry podcast, is Dr Martin Turner who’s an MND researcher, clinician and co-director of the Oxford MND Care Centre.

Having MND mentioned on this podcast is not only great awareness of the disease to everybody who listens to it, but it’s also an opportunity for researchers to disseminate their news in a new and exciting format.

In the podcast, Dr Turner discusses that if physical exercise does increase the risk of somebody developing MND, then a person’s handedness may influence the site of onset due to the motor neurones in the handed arm being used more so than the other arm. However, due to people using both feet (generally) equally while standing etc then there would not be a relationship between footedness and side of onset.

To find out if this was true or not, Dr Turner, and colleagues used to ask 343 people living with limb onset ALS to complete a questionnaire regarding their site of onset and dominant hand and foot. From their results, they identified that there was a link between the side of onset for people who had upper limb onset MND and their handedness. People with a lower limb onset did not have a relationship between their footedness and side of onset as expected.

Dr Martin Turner features on the podcast for about 10 minutes: Listen to the BMJ podcast now: from 8.58 minutes.

Thinking outside the neurone and toward the stars

Neural progenitor cells, courtesy of Chandran lab, University of Edinburgh
Neural Progenitor cells, courtesy of Prof Chandran lab, University of Edinburgh

By using spinal cord donations from people with MND, an American group of researchers have created a new, human ‘in a dish’ model of MND. Their results were published in the journal Nature Biotechnology.

Human neuronal progenitor cells, which have the potential to turn into brain cells but not other types of cell, were extracted from post-mortem spinal cords and programmed to turn into living neurone support cells called astrocytes. The research group, led by Dr Brian Kaspar from Ohio USA, is hopeful that these human astrocytes grown in the laboratory can be used to learn more about the causes of MND.

Astrocytes and MND

Astrocytes, so called because of their star-like appearance, have been known to be involved with MND for many years now. Normally, astrocytes support and nourish nerve cells but in MND, they can become toxic to motor neurones, causing them to degenerate. However, before now, there hasn’t been a way to prove that this really does happen in people as it’s impossible to extract these cells while the person is still alive.

Using post mortem samples to find the answers

This research group used post-mortem spinal cord donations from people with MND to create a new, human astrocyte model, grown in laboratory dishes.

They were then able to demonstrate in the lab that these human astrocytes are toxic to healthy human motor neurones, causing them to degenerate. This verifies that astrocytes can cause MND in people, and not just in animal models.

They then went on to show that the healthy motor neurones could be protected if they stopped a protein called SOD1, which can be faulty in MND, from being created. This was found in astrocytes created from a person with a SOD1 form of inherited MND and remarkably, also from astrocytes created from people with the randomly occurring, sporadic form.

Reaching for the stars

By using post-mortem spinal cord donations from people with MND, and thinking ‘outside the neurone’ this research group were able to successfully create a new human ‘in a dish’ model of disease. There are still many unanswered questions left to explore with this new model, such as how the astrocytes cause the motor neurones to degenerate. By understanding more about this process, new treatments could be investigated to stop astrocytes from being toxic and slow down, or stop MND.

Find out more about tissue donation for general research purposes.


Published in Nature Biotechnology: doi:10.1038/nbt.1957

Read all about the New York Stem Cell Conference

 ….or at least, read even more about it!  

Back in January, we reported that sixty of the world’s leading stem cell research experts from 14 countries were brought together for the first time to shape the development of future international MND stem cell research.

The two-day conference in New York – organised by the MND Association in conjunction with the UK National Stem Cell Network; the Canadian Stem Cell Network; the New York Stem Cell Foundation; and the ALS Association of the USA (ALSA) – brought leading stem cell experts together under one roof in order to agree key areas of investigation in this exciting field of MND research.

You can catch up with what our director of research, Dr Brian Dickie said about the conference in seven Stem Cell Workshop blog posts. 

If you felt that Brian’s daily blogs from the beginning of the year weren’t enough, a more comprehensive report has just been published in the journal Amyotrophic Lateral Sclerosis, of which Brian is a co-author. The journal publishers have also kindly given permission for a version of the report to be available online, which can be downloaded from the ALS Association’s website.

The published report on the ALS Association’s website is not written in plain-english as it provides a thorough assessment of the ‘state of affairs’ of MND stem cell research for scientists – you may find it interesting none-the-less!