In December 2024, we organised the 35th International Symposium on ALS/MND in Montreal, Canada. The International Symposium brings together researchers, healthcare professionals and people with and affected by MND to discuss the latest updates in research. Attendees were able to join many different sessions during the symposium, each one focussed on a different aspect of MND research.
One of these sessions was called ‘Cell Biology and Pathology’ and was a chance to hear the latest work on how MND can affect cells, the basic building blocks that make up tissues and organs. The speakers presented findings on many aspects of cell biology, from blood flow to iron levels to TDP-43, and discussed what this might mean for the future.
Dr Sebastian Lewandowski, from the Karolinska Institute in Sweden discussed how blood vessels are involved in MND. The blood supply to the brain is very important, as it supplies oxygen and nutrients such as glucose which are needed to produce energy. All cells need energy to survive and function, and neurones in particular need a lot of energy to carry out their role. Dr Lewandowski talked about different ways the blood supply to the brain is affected in MND.
The blood brain barrier (BBB) usually blocks things from the blood which could be toxic from getting into the brain. The BBB can become more open, and this might be linked to the onset of MND. Less blood vessels are also seen around the brain and there are bigger spaces between the brain cells and the blood vessels. This means that less blood can get to the brain, and so less glucose and oxygen get to the brain. This may speed up how quickly MND progresses. Dr Lewandowski suggested these problems could be one step along the pathway of developing MND. This could mean that the blood supply to the brain could be a potential target for new MND treatments.
Dr Rachel Tan, from the University of Sydney in Australia presented her work on TDP-43. TDP-43 is a protein which behaves abnormally in the brains of people with both MND and frontotemporal dementia (FTD). Dr Tan’s work focused on identifying different subtypes of TDP-43 behaviour in brain tissue from people with MND. Dr Tan found three different subtypes of abnormal TDP-43.
In one subtype, a small protein called ubiquitin was added to the TDP-43. In the second subtype, there was no ubiquitin added, and in the third subtype there was no TDP-43 present in the brain region that was studied. It’s not clear at this stage what these subtypes might mean and whether they could be linked to symptoms or disease progression. Further studies should focus on investigating if there is a link between the different subtypes of TDP-43 and clinical symptoms of MND. These findings could help to find new biomarkers for MND and could provide a new target for MND treatments.
Dr Holly Spence, from the University of Aberdeen in the UK, talked about how iron levels are affected in MND. Recently, a signal was reported on MRI scans of people with MND, called a ‘motor band sign’. This is an indicator of iron in the brain and was present in 59.6% of people with MND in the study. Dr Spence investigated iron in brain tissue from people with MND by looking at ferritin – an iron storage molecule that stores iron in its most stable form. 57% of the tissue looked at was high in ferritin – this matches the percentage of people with MND who had motor band sign.
Dr Spence also found that in people with high ferritin, there were lower levels of several other chemicals including a chemical called cysteine, which could lead to further damage to the cell. A potential treatment which increases cysteine levels, and has also been shown to prevent TDP-43 buildup, underwent clinical trials in the 1990s but did not have a strong enough effect to be approved for MND. Dr Spence suggested that motor band sign on MRI scans could be used as a marker to identify people with MND who have increased ferritin and lower cysteine, who may benefit from this treatment the most. This type of targeted selection of people for clinical trials could improve the likelihood of a clinical trial being successful.
Dr Cláudio Gouveia Roque, from the New York Genome Centre in the USA, delivered a talk about problems in genes, and whether different problems occur in people with MND who also develop problems with language and thinking. The researchers used brain tissue from people with MND who had problems with language and thinking, and from those who didn’t. They looked at two different areas of the brain, as well as different types of cells.
Interestingly, they found different gene problems between people who had language and thinking problems and those that didn’t, but also found differences between the different brain regions and different types of cells. This has furthered our understanding of the processes underlying memory and thinking problems in MND, and highlighted specific differences between them. This could be a target for future treatments.
Dr Rebecca San Gil, from the University of Queensland in Australia discussed her work on the effect that TDP-43 has on other proteins in MND. She used mice which had been genetically altered to produce human TDP-43 to see how the behaviour of other proteins changed during the disease. She found changes in several other proteins, including chaperone proteins. Chaperone proteins help other proteins to fold into the correct structure for them to carry out their jobs.
One of these chaperones was called DNAJB5. When DNAJB5 was investigated further, it was present in the same places as TDP-43, suggesting it may influence the behaviour of TDP-43. To investigate this, Dr San Gil removed DNAJB5 from cells which led to more abnormal TDP-43, and worsened MND-like symptoms. On the other hand, increasing the levels of DNAJB5 led to less abnormal TDP-43. This suggests that DNAJB5 may play a role in disease progression, and increasing DNAJB5 could be a target for future treatments for MND.
The work described in these talks has improved our knowledge of the cellular processes underlying MND. It is important to have a good understanding of these processes; if we understand what is going wrong, then this will improve our chances of finding an effective treatment in the future.
