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.

The other theory is that the spread of the disease could be dictated by chemicals released by other cells in the central nervous system, in particular the glial cells, which may outnumber the nerve cells in the human CNS. The word ‘glia’ comes from the Greek word for ‘glue’ and was so named by neuroscientists in the 19th century as it was believed that they basically acted as the ‘filling’ of the brain to hold the ‘wiring’ of the nerve cells in place.

However, it has since become clear that they play a much more important role in helping to support and protect the neurons….. at least most of the time. Research over the past decade has shown that they have a darker side – a so-called ‘activated state’ – which can have the opposite effect and cause damage to neurons in the cellular neighbourhood.

Although both theories are still very valid, with ongoing research presented at the recent 28th Symposium, the role of glial cells formed the theme for Session 9A on the last day of the meeting. There are several types of glial cells found in the CNS, but researchers have largely focused their attention on two particular members of the glial cell family: astrocytes and microglia.

Advances in neuroimaging

Courtesy of Dr Nazem Atassi (Jucaite A et al. Brain 2015)
Courtesy of Dr Nazem Atassi (Jucaite A et al. Brain 2015)

Dr Nazem Atassi (Harvard) kicked off the session by showing the latest neuroimaging techniques that are being applied to measure the amount of glial activation that is occurring in people with MND. Using a combination of cutting-edge positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques, he was able to show that in ALS and PLS (a rarer form of MND) patients, the activity of glial cells in the brain was significantly increased in areas where nerve damage was occurring and that this also correlated with the clinical measures of the disease. He also showed some preliminary results of an ongoing study showing increased glial activity in the spinal cord – an incredibly technically challenging piece of work. To show that PET imaging of spine is feasible is an exciting advance.

So – in a nutshell, these imaging studies show that what is happening ‘on the inside’ is reflecting the physical changes ‘on the outside’.  Dr Atassi intends to further refine these techniques so that they can be incorporated into future clinical trials, in particular for drugs aimed at targeting the glial cells.

The importance of astrocytes

The potential role of astrocytes in causing motor neuron death was explored by Dr Laura Ferraiuolo (Sheffield) who has developed an elegant laboratory technique that allows mouse motor neurons and human astrocytes (created from human skin cells) to be grown together in a dish, but separated by a porous membrane that allows chemicals released from the astrocytes to travel across to the motor neurons.

Using this technique, the Sheffield team developed a theory that astrocytes from ALS patients might release chemical factors that are toxic to motor neurons. These factors may be contained within structures called extracellular vesicles (EV) that cells appear to use to ‘eject’ unwanted substances. In trying to work out what these factors are, they focused on a series of molecules known as ‘microRNAs’, measuring the types that were released by C9orf72 patient’s astrocytes compared with control (non-ALS) astrocytes.

They found that the C9orf72 astrocytes released fewer EVs, which was associated with a significant reduction in the release of two particular microRNAs from the cells. Moreover, by supplementing these microRNAs directly into the dish, they could improve the health of the motor neurons.

In the light of these results, their initial theory that a toxic factor may be involved has been somewhat ‘turned on its head’ to a new theory that the damage to motor neurons may be due to the loss of essential survival factors, such as microRNAs, which are released by astrocytes. If this is the case, then in might be possible to use gene therapy approaches to increase the levels of these microRNAs and keep the motor neurons in a healthy state.  Their next step is to find out whether this effect only happens in C9orf72 ALS or in all forms of the disease.

Dr Laura Ferraiuolo, University of Sheffield
Dr Laura Ferraiuolo, University of Sheffield

Moving on to microglia

The final two speakers in the session focused on the other likely glial culprit, the microglial cell. The brain does not have the sophisticated immune system that is found in the bloodstream and other parts of the body, but it does have its own version in the form of these cells, which form the first line of defence against invaders. Unfortunately, they do have a tendency to become overactive, giving rise to a lot of collateral damage to neurons.

Dr Fei Song (Chicago) outlined how motor neurons communicate with microglia. She has previously shown that in the SOD1 mouse model of ALS as well as in human post mortem ALS tissue, this overactivity may be mediated though proteins (called neuregulin receptors) on the surface of microglial cells.  In her presentation in Boston, Dr Song outlined how she and colleagues have developed a large protein-based molecule that blocks the neuregulin receptors. Administering this molecule directly into the spinal fluid of SOD1 mice reduced the activity of the microglia, delayed the onset of disease and increased survival.  This may open up a new therapeutic approach, though as we know from hard experience, approaches that appear to work in the SOD1 mouse have invariably failed when trialled in man, so there is still a lot of work to do be done if this is to be taken into clinical trials.

In addition to their immune-like role when they become activated, microglia also appear to have a day-to-day role in clearing up unwanted debris in between cells. Dr Marco Morsch (Sydney) showed that microglia can help to mop up proteins such as TDP-43 when they leach out of sick or injured cells.

Dr Morsch showed a series of studies using an embryonic zebrafish model, which allows individual neurons to be studied in the living animal. The fish were genetically modified to produce human TDP-43 (a protein linked to over 95% of ALS cases) and in these animals he was able to show how microglia are attracted to sick or damaged neurons and help to clear up any TDP-43 that is leaking out of these weakened neurons. If the microglia were absent, the damage was much more severe. These findings indicate that microglia may also play a role in the first theory of disease spread (mentioned at the beginning of this article) by helping to stop damaged proteins from sick neurons ‘infecting’ their neighbours.

In turn, this suggests that any drug therapy that targets microglia might work best if it can effectively stop the microglia from becoming activated and aggressive, but not to the extent that it stops these essential cells from doing their day job of hoovering up cellular debris.

3 thoughts on “It’s not just about the neurones

    • Thanks Mike – I wouldn’t want to perpetuate out of date (and incorrect) information. I have altered the text accordingly.

      Brian

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