Background
Background: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a neurodegenerative disease that is caused by the death of motor neurons. This causes progressive paralysis that is very life limiting. Studying and understanding ALS will hopefully lead to treatments for patients. ALS can be caused by inheriting mutations in specific genes, with 4% of inherited cases resulting from mutations in the FUS gene. Genes are instructions for proteins that our cells need, meaning mutations in the gene results in proteins that also contain the mistake. This can negatively affect the protein’s function. The FUS protein is involved in many cell functions, including DNA damage repair. Mutant FUS protein in ALS can sometimes mean that it ends up in the wrong part of the cell, where it can clump together forming aggregates that are toxic to the cell.
Motor neurons are not the only cell type affected in ALS. Non-neuronal cells known as astrocytes are also involved in ALS. Under healthy conditions, astrocytes are vital for keeping neurons functioning correctly. In ALS, astrocytes can become toxic and have negative effects on motor neurons. Studying the effects of mutant FUS in astrocytes alone would provide insight into how this mutant protein can impact motor neurons. This could show how astrocytes have the potential to be targeted in ALS.
Why is the study important?
Focussing on the effect of mutant FUS in astrocytes alone can isolate the impact that these cells might have in ALS, making it easier to identify a potential treatment target. This would be of benefit for patients with ALS, as there are currently very few treatments available.
What did the authors do and how did they do it?
To study the effects of mutant FUS in astrocytes alone, they devised an injection that allowed the mutant FUS to be present only in astrocytes in otherwise healthy mice.
What are the results?
The mutant FUS in astrocytes resulted in death of motor neurons in the mice, as well as problems with their motor functions. To find out what might be causing this, the researchers measured the amount of the inflammatory molecule, TNFα, which was present in the mice. Similarly to how physical injuries become inflamed, our brains and spinal cord can also have inflammation if we have a disease. Inflammatory substances like TNFα that contribute to inflammation are not always detrimental; we need some inflammation for our injuries to heal, for example. However, in some diseases, such as ALS, the amount of inflammation in our brains and spinal cord can be harmful to cells. It was found that the mice with mutant FUS in their astrocytes had a lot more TNFα than mice with healthy astrocytes. To confirm that it was the increase in TNFα that was causing the symptoms in these mice, the researchers blocked TNFα with antibodies. This helped protect motor neurons and improved their motor functions, though the effect was not long term. It showed that the mutant FUS in astrocytes causes an increase in TNFα, which is a direct cause of motor neuron death in these mice.
What do the finding mean going forward for people with the disease?
Showing that mutant FUS in astrocytes can cause an increase in TNFα, leading to motor neuron death and symptoms in mice was an important finding. As the researchers showed, blocking TNFα helped improve symptoms in these mice for a time, potentially highlighting this a treatment target for ALS patients with FUS mutations. The treatment would also need to be optimised further in mice to see if it could work longer term. For patients with ALS who have FUS mutations this could potentially be a treatment in the future, however it is not known if this would be helpful for other ALS patients.