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 »

Can zebrafish help us to learn more about MND?

A team at the Sheffield Institute for Translational Neuroscience are creating a zebrafish model to study the C9orf72 gene mutation in MND, and work out its role in the brain and spinal cord (our reference 864-792).

Zebrafish are a good way of modelling what happens in human MND. We know that many of the genes linked to causing MND in humans are also found in zebrafish. For example, changes to a gene called SOD-1 in humans are linked to about 20% of all cases of inherited MND, and when you genetically change the same gene in zebrafish they develop symptoms similar to MND.

A faulty or changed C9orf72 gene is associated with about 40% of all cases of the inherited form of MND. This change (or mutation) is also found in people with a form of dementia called frontotemporal dementia (FTD). FTD can alter abilities in decision-making and behaviour.Read More »

Finding a connection between the cell’s waste disposal system and MND

Just like when we put out our recycling every week, the cells in our body have their own recycling system too. One of the recycling plants within our motor neurones works by a system called autophagy. In a recently completed research project that the MND Association has funded Dr Rob Layfield and Dr Alice Goode have been looking at how malfunctions in autophagy cause MND (our reference 821-791).

Their research has focussed on how a gene called SQSTM1 and the protein it makes (the protein is known as ‘p62’) is involved in MND. The project has gone well and we have a much better understanding of how cell recycling goes wrong in MND.Read More »

Using fruit flies to understand a genetic cause of MND

Mistakes in a gene known as ALS5, or spatacsin, cause a rare form of inherited MND that develops at a much earlier age than most other forms of the disease. Under supervision from Dr Cahir O’Kane, MND Association funded PhD student Alex Patto has been using fruit flies to understand how mistakes in spatacsin cause MND (our grant reference 861-792).

Prior to this research, which is based at the Department of Genetics at the University of Cambridge, nothing was known about how faulty spatacsin leads to motor neurone degeneration. Three and a half year years on, this research has shed light on this important question.

What did they find?

By conducting tests in the fruit flies, Alex has found that the spatacsin protein has a role in cell recycling (also known as autophagy), a process which keeps cells healthy. When the spatacsin protein is faulty it leads to disrupted cell recycling and abnormal levels of another protein called Rab7, which might contribute to MND development.Read More »

Mastering Pac-Man

Growing up in a seaside town in the 1980s led to me spending a lot of my “formative years” in the local amusement arcades, playing iconic video games like Space Invaders (at which I was average) and Asteroids  (I was the kid to beat!). One game I never got the hang of was Pac Man, where you had to guide a munching yellow ball around a maze eating up lots of dots. I even bought a book ‘Mastering Pac Man’ which didn’t help much – I was just plain rubbish!

Pac Man chasing Dr Brian Dickie
Dr Brian Dickie and Pac Man

Talking about rubbish, fast forward 30 years and Prof Anne Simondsen from The University of Oslo is on the platform in Chicago describing the ways in which neurones deal with their cellular rubbish, such as poorly manufactured or damaged proteins.

Much as the dots are gobbled up by Pac Man, so cells employ a couple of basic ways to dispose of and recycle damaged proteins. One is a process called proteasomal degradation, which has been discussed on this website before by one of our guest bloggers, Prof John Mayer. However, some proteins, especially protein aggregates, are a bit too large and tough to be broken down by the proteasome, but they can be degraded by another process called autophagy – which can literally be translated as ‘self-eating’.

Prof Simondsen explained how aggregated proteins and even larger cellular structures can be packaged up for destruction by being encapsulated within membranes, forming structures called autophagosomes. These in turn seek out a structure called the lysosome, which contains digestive enzymes which break down the protein rubbish and keep the cell ‘spick and span’.

Using studies involving fruit fly models (a favourite model for cell biologists) she showed that the autophagy process declines with age, which is unfortunate because protein damage tends to increase with age. It was therefore no surprise that the level of autophagy in the brain was directly associated with the accumulation of protein ‘inclusions’, the health of neurones and the life expectancy of the flies.

Much of the evidence supporting a role for autophagy in neurodegeneration comes from the field of Huntington’s disease. Prof Simondsen explained how a particular mutated protein – called huntingdin – accumulates in the dying neurones and is a classic pathological hallmark of the disease. She demonstrated that autophagy normally plays a central role in the disposal of damaged huntingdin, but the system simply cannot cope with the amount of damaged protein, which starts to accumulate and literally ‘gunge up’ the cell. However, by stimulating the manufacture of additional autophagy machinery, the amount of aggregated protein can be reduced, helping to protect the neurones. This has so far only been shown in simple lab models of Huntington’s disease, but the encouraging results mean that further development to try and develop a treatment is underway.

So, could a similar approach be useful in other neurodegenerative diseases such as MND? Certainly, for some types of MND, such as those linked to a rare gene mutation called CHMP2B, it appears that a component of the autophagic machinery is impaired, which leads to protein build-up in cell models.

Dr Eiichi Tokada (Umea University, Sweden) provided further evidence that autophagy plays a role in disease progression in the SOD1 form of MND. By switching off a crucial component of the autophagy machinery, the disease progression in SOD1 mice was accelerated and their lifespan shortened. In addition, when he examined the spinal cords of the mice, he saw an increased presence of the characteristic SOD1 protein aggregates – a pathological hallmark of the disease.

Dr Faisal Fecto (Northwestern University, USA) provided evidence from a third genetic cause of MND. He showed how mutations in the Ubiquilin 2 gene disrupt the autophagy pathway by stopping the autophagosomes from linking up with the lysosomes.

So, it certainly seems that autophagy has a role to play in some of the rarer familial froms of MND. It remains to be seen to what extent it is involved in MND more generally, but it may mean that the potential treatment strategies being developed for Huntington’s disease may offer future opportunities for MND as well.

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