The season of the gene

“Welcome to this afternoon’s genetics session, which I hope will convey elements of hope and excitement about the season of the gene” were Professor Teepu Siddique’s (from Northwestern University, USA) opening remarks on a series of talks that really did live up to this standard. To me each talk was like being read chapters of a thriller novel, each was gripping with its own story to tell, but by the end of the session I was really buoyed up with hope, enthusiasm and an appetite for more!

Prof Siddique’s research lab have contributed two important new discoveries in MND genetics in the last few months alone (UBQLN2 and SQSTM1), so he was very well placed to begin with an overview of how recent discoveries allow us to make sense of much of what has been to date.

Prof Siddique started his talk by discussing what we can tell about MND by looking at human motor neurones down a microscope . Using some very elegant studies of the build up and removal of proteins tagged with different colour labels he demonstrated that many causes of MND (ie genetic mistakes in TDP-43, SOD1 and FUS genes, and the randomly occuring sporadic form) all have a build up of ubiquilin2. The next part of the story was to explain what this protein was doing there – what sequence of events or malfunctions in the motor neurone has caused the protein to be there. Time and again he demonstrated that at the heart of disease-causing damage in MND is the protein recycling system (see Prof Mayer’s post a month or so ago). This was summed up for delegates by playing a TV commercial of blindfolded women trying to identify different parts of an animal (a rhino this time) and only when their blindfolds were removed was the whole story revealed.

The phrase an ‘elephant in the room’ is used in reference to the presence of a huge topic that no-one is talking about. But the huge topic in genetics was most definitely getting an airing this afternoon – that of the discovery of the C9orf72 gene defect. Speakers either talked about it in light of the way that it links together a number of diseases where there is evidence of frontotemporal dementia as well as signs of motor neurone damage. Or the fact that the actual gene defect seen in C9orf72 is so different to older genetic discoveries in MND – in so much that the damage is caused by lots of extra letters included in the instruction, rather than a ‘spelling mistake’ in the instruction by removing, substituting or deleting individual letters. Now that genetic researchers are tuned in to looking to genetics in a new way and looking for changes in new places, it seems that there is a huge potential to make discoveries and connections that much faster. Personally I can’t wait to read the next instalment.

Read our official press release from day two of the symposium.

Beauty and the Beast – when misfolded proteins cause havoc

Beauty is often said to be skin deep, but in terms of proteins, their appearance means everything. Its appearance and shape denotes its role in our cells and allows it to attach itself to other proteins and parts of the cell to perform its role. If its appearance is significantly altered through misfolding, turning it into a ‘beast’, it can no longer perform its role properly, rendering it useless. Not only does this mean that a protein’s regular role is not being performed, but it also means that there could be a build up of beastly, misfolded proteins in the cell, if they are not recycled efficiently. Misfolded proteins was the topic of discussion at one of this afternoon’s sessions of the symposium – topics ranged from the machinery or location involved in the folding to which proteins, SOD1 and TDP-43 among them, are being misfolded and why.

Protein Origami

When our proteins are first built in our cells, they can be related to a piece of paper. On its own, it can’t perform its regular function so it needs to be folded into its final form – in this example, a paper aeroplane. To do this, it is fed inside a network of connecting tube like structures called the endoplasmic reticulum – or ER for short, where it is folded and sent to its final destination to perform its role within the cell.

This everyday process within the ER can become stressed when misfolded proteins build up inside which triggers a response to try to restore order. Our cells cannot maintain this for a long period, which isn’t normally a problem as ‘regular’ issues are short-lived. However, when proteins are regularly misfolded in diseases such as MND, this can cause pandemonium as the response that normally restores order cannot cope with the sheer volume of misfolded proteins, which causes the motor neurones to degenerate.

Stressful response to MND

In the first presentation of this session, Dr Julie Atkin from La Trobe University, Australia discussed how there is increasing evidence to suggest that ER stress is linked to MND. Although ER is found in every cell in our body, little is understood about it in neurones. In a previous study, her laboratory demonstrated that ER is actively trying to restore order, both in the spinal cords of mice that model the disease and people with MND. This response is one of the first MND causing events to occur in a mouse model. Dr Atkin’s current area of study is centred on understanding how this response is activated in MND. In her overview she demonstrated that many of the damaged proteins recently associated with MND cause ER stress.

Their most recent studies have suggested that issues with transport away from the ER could cause the build up of misfolded proteins leading to stress and a response to restore order. Understanding how the ER stress response is activated could be important in order to device new treatments that target this system, stop the neurone from being stressed, and potentially stop it from dying.

The next few talks moved to looking at how and why some of these proteins may become unfolded and how this is helped by the cells’ coping and balance-maintaining systems. 

The beginning of Nic Dokholyan’s talk really made me sit up and take notice, no cell pathway diagrams (cartoons), no images or cells fluorescing different colours under a laser microscope and no ‘blots’. It was a cartoon of an elephant, representing the Chinese proverb of a blind man and an elephant.

 He explained that this represented his impression of the knowledge of the MND research community, after attending the International Symposium on ALS/MND in Berlin two years ago. Everyone knew their own particular part of the elephant (or the underlying cause of MND) really well, but no-one had put all the bits together to get the overall shape / see the whole cause of MND. Doing a rough assessment of all of the known causes of MND (via a method he described but I didn’t quite catch or understand –probably the latter!), he concluded that SOD1 misfolding should be at the centre of the ‘elephant’. Results showing that copies of SOD1 protein are modified in blood samples from people who do not have MND (including a sample of his own) was the starting point for the research he presented in Sydney. Dr Dokholyan’s went on to describe a series of elegant techniques demonstrating how a very minor, small alteration to the surface of a protein can affect its ability to misfold and accumulate within motor neurones. (Perhaps going back to the earlier beauty analogy, this is the equivalent of having a mole or facial blemish removed.)

Read our official press release from day two of the symposium.

If you were a car, would you be a Ferrari or a Focus?

People at increased risk of MND might be the human equivalent of high performance cars – built for speed and agility but becoming unreliable once they reach a high mileage.

There is much anecdotal evidence amongst MND clinicians and those affected by the disease that people who develop MND tend to have been relatively physically fit before their diagnosis, often having been involved in various athletic pursuits throughout their life. This prompted MND Association-funded researcher Dr Martin Turner to ask the intriguing question: Is an athletic physique an outward sign of a subtle predisposition to MND? But how could he make a sensible measurement of ‘athletic physique’ in order to answer such a question? Or as he put it in his presentation on Thursday morning, do people with MND have motor system run to death, or is it a motor system born to run?

A pragmatic way of looking at this was to look at the history of coronary heart disease and whether this is linked to a likelihood of developing MND later in life. Dr Turner has recently published this study in the Journal of Neurology, Neurosurgery and Psychiatry). Through very careful examination of hospital medical records, he and his colleagues compared numbers of MND cases in over a hundred thousand people with a history of coronary heart disease to an even larger group with no known heart problems.

The study did reveal a slightly increased occurrence of MND in the group with healthy hearts, providing indirect evidence that MND is more likely to occur in people with greater levels of ‘fitness’. Dr Turner’s results were in fact corroborated by the findings of another more general study of lifestyle and environmental factors presented in the same session. Dr Marc Huisman’s meticulously executed and much admired questionnaire-based study of the Dutch population also suggested that people with MND were less likely to have relatives with heart disease, indicating a more genetically robust cardiovascular system, amongst many other findings.

Dr Turner’s findings are intriguing but there is still plenty more work to do and many questions are left unanswered. There are other studies that support the possibility of an increased MND risk in people with a healthy cardiovascular system and lean build but of course these two characteristics are also a result of undertaking higher levels of exercise – the question of whether exercise itself contributes to MND still won’t go away. However, Dr Turner’s work supports the concept that if you’re born with a natural leaning towards athletic prowess, you may excel at sport (or in evolutionary terms, hunting down your dinner) but your nervous system wiring may also be more vulnerable to MND as you age – a factor that’s only become problematic with the dramatic increases in life expectancy that have come about in the last couple of hundred years.

As Dr Turner put it at one our spring conferences this year, people with MND may well come from amongst the Ferraris of the human race. With clearer identification of risk factors, prevention of MND becomes a more realistic possibility. It may be that in future the Ferraris can undertake a specialised servicing schedule to ensure they have a greater chance of breaking the 100,000 mile barrier with their electrics in good working order!

Read our official press release on day two of the symposium.

Copying, transporting and creating proteins – what could possibly go wrong?

Proteins are the building blocks of our cells and have a variety of important roles within our bodies. The instructions for how to build our proteins sit within our DNA, our genetic code in the control centre of our cells (the nucleus). There are many steps to go through from reading that ‘raw’ instruction to ending up with a fully functioning protein.
However, the amount of information held within our genetic code is so huge that only small segments of it are read and transferred to the factory floor, as and when they are needed. These copies, known as messenger RNA, are small enough to be transported to the ‘factory floor’ of the cell to large machine-like entities called ribosomes where the copy is read, and used to create the resulting protein.
When I was doing my A levels and later at University (yes, that long ago!), we were taught that only 1% of the genetic code ever made it to the factory floor. This held true until a couple of years ago. However, as explained by Professor Bob Brown in his presentation at the ‘RNA and protein processing’ session this afternoon, such is the change in our knowledge in that area, we now know that 95% of our genetic code makes it through to the first step of making proteins.
This was a key piece of context in trying to understand the role that TDP43 plays in functioning cells – never mind specifically in motor neurones or in cases of the presence of damaged TDP43 in MND!
Professor Brown, University of Massachusetts Medical School, Boston, USA went on to give an enlightening review of what has been uncovered about this fascinating protein (TDP43) so far. Once the protein of TDP43 has been correctly made, its function is to go back and ensure that other proteins are correctly made too – the so called ‘reading helpers’ of the cells, or ‘editors of instructions’. Another new fact to me from this talk was that TDP43 is involved in editing or reading up to ONE THIRD of all proteins within the cell. That’s a city fat cat type of job! So how is it all related to it’s function in MND?
Some elegant experiments have shown that TDP43 regulates how many copies of it’s own protein are made. However, the regulation takes place in the control centre of the cell (see the top of this blog). If TDP43 gets stuck or waylaid on the factory floor, it can’t get back to press the stop button in time. So it’s thought that more and more protein is made, accumulating on the factory floor until that accumulation can be seen as the protein deposits so characteristic of what you see of motor neurones affected by MND down the microscope.
Part of the editing work that TDP43 does so well is known as ‘splicing’. In true ‘Blue Peter’ style, here is a description of that process that Kelly prepared before I flew out to Sydney:

Alternative protein
One gene can hold the instructions for a number of different versions or variants of a protein. These variants are created when different parts of the gene are used in alternative combinations. This is a normal process and it’s called ‘alternative splicing’. This complicates matters in terms of genetic research, as even though we have approximately 20,000 genes, we could potentially have a much higher number of functional proteins because of alternative spliced variants.

How does alternative splicing work?
The picture (below) depicts a simple version of how a gene can be alternatively spliced, given three ‘parts’. The example demonstrates that the first version of the protein is made up of parts 1, 2 and 3, whereas version two is made up of only parts 1 and 3. These resulting proteins would go on to function in our bodies in potentially different ways. It is therefore possible for a number of different proteins to be created given one set of original instructions in the genetic code.



Read our official day one symposium press release on our website.

Rip roaring start to Symposium

Entering the room for the opening session of the International Symposium on ALS, there was a real air or anticipation. Organisers (yes, that included you, Brian!) nervously pacing back and forwards, checking final details and greeting old friends and colleagues. Then Wim Robberecht, chair of the Programme Committee, called us all to order. A ripple of murmuring and camera flashes from the back of the room drew our attention as Glen Doyle on behalf of the Gadigal tribe welcomed us to Sydney by playing the didgeridoo and singing us a welcome song. Dressed and decorated in a traditional manner it was a stunning start to the meeting!

We heed the invitation of the President of MND Australia, Ralph Warren, to learn and participate in the deliberations, by absorbing the excellent talks of the two opening speakers. (Yes, there was a third presentation too, but more of this later).

Prof Ravits gave us an insight into what may be causing the differences that we see in people with MND. As he said himself, he started his talk in the most fitting way – by starting with one of his patients, describing their symptoms over the progression of their illness. Even for people with the form of MND known as ALS (or amyotrophic lateral sclerosis) each person develops the disease in a different way – why?? Prof Ravits has identified a broad two stages of disease – an early stage, where the symptoms are separate and very specific and a later stage where there is generalised damage to motor neurones and a broader range of symptoms. On a cellular level, these symptoms are reflected in ‘trigger’, ‘propagation’ and ‘neurone death’ stages of disease. Learning more about the early stage of the disease may give us opportunities to target specific treatments to the area of motor neurone damage, he concluded.

The theme of a trigger for motor neurone damage dovetailed the presentations of John Ravits and the next speaker, Garth Nicholson together. In a spectacular video involving a chain reaction of ping pong balls being released from a large table of loaded rat traps, Prof Nicholson highlighted that a trigger event is needed in all forms of MND –whether it is the rare, inherited form of MND or the more common sporadic disease. In the video, this trigger was a colleague throwing a single ping pong ball on to the table, triggering all of the other balls to be released and fly everywhere (with the initiator cowering in the back of the room to protect himself from the flying balls!). He is optimistic for the future of MND research in finding these, as yet unknown triggers of disease.

Read our official day 1 press release on our website.

Tuesday evening – the night before Symposium

At 6pm this evening, there was a real air of anticipation at the conference hotel. On level 2 the poster presenters were gradually finding their allocated slots and gaps were being filled. Up the escalator on level 3, the registration desk has now closed for the night. It will open again at 6am in the morning, ready to register another few hundred delegates. The lanyards are neatly rolled, the bags stacked tidy and ready for their eager recipients. A snake of coffee cups is ready for that all-important mid-morning energy boost.

Getting into the lift is like entering a who’s who of the MND world, international scientists and clinicians greeting each other and exchanging stories on jet lag, holiday plans and of course the results from their lab or scientific gossip.

As well as soaking up this atmosphere, today I’ve been busy putting Kate and Kelly’s plans for the poster session into action. The poster session is arguably the most interactive part of the meeting, an opportunity to share a hard copy of your presentation with a (possible) 600 people is valuable. They may pass on the next tips to helping get that experiment to work or you may set up a new collaboration or redirect your research. However, in order for this all to happen, 300-ish 2m high and 1m wide boards, need to be individually assigned to specific posters, in an order that (I hope) the delegates will follow. Thanks to Harriet for all her help with sorting this out.

Across the road from the hotel is the Queen Victoria Building shopping arcade. It is beautifully decorated for Christmas – there are only a few weeks to go. But for Symposium delegates it is only one more sleep before our excitement begins!