We organised the 35th International Symposium on ALS/MND in Montreal, Canada, back in December last year. The symposium provided an opportunity for researchers, clinicians and people living with and affected by MND from across the globe to come together and share all the latest updates in MND research. Sessions were held for many different topics, allowing those interested in a specific area of MND research to come together and hear about some of the exciting projects and, most importantly, ask lots of questions! Glial cells took centre stage during one of the sessions on the first day. In this blog, we will give you a summary of all things glia presented in the session.
Lets talk about glia…
Before we start, let’s first have a run-down of what glial cells are. The term ‘glial cells’ is a bit of an umbrella term that includes different cells that support motor neurons in the brain and spinal cord. They each have similar but specific roles in keeping the neurons, and the environment in which they are found, healthy and supported. In MND, we know that motor neurons are not the only cells that stop working properly, and glial cells are likely to contribute to motor neurons dying.
The diagram below introduces microglia, astrocytes and oligodendrocytes, which are important glial cells in the brain and spinal cord, and gives an overview of how they support the motor neurons:
Now that we know the basics of glial cells, let’s dive into the exciting talks presented at the symposium, which shine a light on how glial cells may be involved in MND.
Oligodendrocytes
Firstly, Katherine Lewis, a PhD student at The Florey Institute in Australia, opened the session with a fascinating talk about the role of myelinating cells in MND. Katherine’s research explores the behaviour of myelinating cells, including oligodendrocytes, in a mouse model of MND caused by a mutation in the TDP43 gene. She presented some interesting data suggesting that myelinating cells do not work properly in the later stages of disease.
The cells stop making some of the important proteins that help them to keep their structure, stop folding around neurons correctly and also show higher levels of cell death. Now, Katherine’s research is focused on understanding whether changes to myelinating cells are causing, or caused by, damage to neurons in MND. If these cells are contributing to neuronal damage, they may prove to be a good target for therapeutic intervention in MND.
Astrocytes
Following this talk, two talks were given from postdoctoral researchers from the University of Sheffield about their work exploring astrocytes, one of the supporting glial cells in the brain and spinal cord, in MND. Both Dr Monika Myszczynska and Dr Marianne King use stem cells in their research. This means that they use skin cells from people with MND, and healthy controls, and turn them into the cells that they want to study, such as astrocytes and motor neurons. Both researchers use cells from people with mutations in the C9orf72 (C9) gene. Mutations in this gene are linked to MND and frontotemporal dementia (FTD), although what makes someone develop either MND, FTD or both, remains unknown.
Monika’s research looks at how astrocytes from people with C9 MND behave differently from astrocytes from people with C9 FTD. She found that when motor neurons were grown with C9 MND astrocytes there was more motor neuron death than when the motor neurons were grown with C9 FTD astrocytes. This showed that the astrocytes from people with C9 MND were toxic to the motor neurons but the astrocytes from people with C9 FTD were not.
To understand why this may be, Monika found that the levels of some important genes in the motor neurons were being changed when they were grown with the MND astrocytes, but not with the FTD astrocytes. This work is helping us to understand how some people with mutations in the C9 gene may develop MND, while others may develop FTD, and some develop both.
Marianne’s work explores the role of a lesser known MND risk gene, WDR49, in driving motor neuron death in MND. She presented interesting research showing that C9 astrocytes did not have as much WDR49 as healthy astrocytes. The lower levels of WDR49 seemed to correlate with the higher amount of motor neuron death seen when the astrocytes were grown with the motor neurons. This data supports the idea that WDR49 is protective in MND, which is now being further explored. This could place WDR49 as a potential therapeutic target in MND.
Microglia
Dr Jasna Kriz from Université Laval, Canada, then pivoted the session towards talk of microglia, which are the immune cells of the brain and spinal cord. When a gene is expressed in a cell, it means that the gene is turned on and it will be made into RNA, which contains a list of instructions for how to make a particular protein. The RNA can then be made into protein within the cell, as per the instructions ‘written’ in the RNA. Normally, if the expression of a gene is high, the amount of protein will also be high. However, Dr Kriz explained in her talk that the link between gene expression and protein expression in microglia cells is broken in MND.
Using a mouse model of MND caused by mutations in the SOD1 gene, she found that while the expression of some protective genes was UP, the amount of protein made from these genes was DOWN. This disrupts the balance of protective and harmful signals in microglia and makes them too aggressive towards other cells, such as motor neurons. She identified an important gene in the microglia that might be causing the link between gene and protein levels to break. Now, her work explores the possibility of targeting this gene therapeutically in MND to try and stop this from happening.
Also sticking to the theme of microglia, Dr Björn Vahsen, from the University of Oxford, then shared some exciting findings about the interactions between microglia and motor neurons in MND. Björn’s research, which is funded by the MND Association, uses stem cells from people with MND who have a mutation in the C9orf72 gene, similarly to Monika and Marianne’s research. However, instead of converting the cells into astrocytes, Björn converts the cells into microglia and motor neurons. By combining healthy neurons with MND microglia, and vice versa, he was able to explore which cells might be driving changes in MND.
Björn shared fascinating data suggesting that both microglia and motor neurons behave differently when grown together, compared to when they are grown by themselves. When grown together, he saw changes to the connections between the cells and the way that the cells responded to different signals. These changes appear to be driven by the motor neurons, but dependent on the presence of the microglia. This research is helping to understand how different cell types communicate in MND, which is important for finding new ways to target the disease. You can read more about Björn’s research here.
Finally, Dr Dominik Feurerbach, an Associate Director at the pharmaceutical company Novartis, closed the session with a talk about changing the behaviour of microglia so that they become more protective towards other cells. Receptors are specific types of proteins that are found on the surface of cells, and they detect and respond to different signals in the environment. It is already known that activation of one of the receptors on microglia, called TREM2, instructs microglia to be protective towards other cells.
Dominik shared pre-clinical data about a new drug, called VHB937, which is designed to target the TREM2 receptor on microglia. The drug was found to improve the ability of microglia to clean up dead and damaged cells in the brain and improve the survival of motor neurons in different models of neurodegeneration. This drug is currently being tested in a phase 2 clinical trial, to see if it could be an effective treatment of MND. You can find out more about the trial here.
We hope that this blog has given you a bit of an insight into some of the exciting glia research that was shared at the 35th International Symposium on ALS/MND. These research projects, and many other projects displayed on posters at the Symposium, are helping us to understand the role of glial cells in driving MND, and whether they can provide promising therapeutic targets for treating MND. This work is helping in the journey towards a world free of MND.
