The exact course, duration and rate of progression of MND often varies greatly from person to person; even when there is a known family history of the disease caused by a specific MND-causing gene (eg SOD1).
This same variability also occurs in mice. Researchers, funded by the MND Association, took two mice with the same SOD1 gene mutation from two different families (strains). By using these two mice the researchers identified a number of key changes in motor neurones that differ between fast and slow progressing forms of the disease.
Two mice… One gene
Developing new disease models enables us to both understand the causes of MND and test potential new therapies.
Mice are commonly used in MND research and for the past 10 years or more, the SOD1 mouse model has been one of the most important research tools for scientists working in the field, particularly with testing potential new therapies.
Research published in September 2013 was carried out in a joint collaboration between Dr Caterina Bendotti (Mario Negri Institute for Pharmacological Research, Milan Italy) and Prof Pam Shaw (University of Sheffield, UK).
Two very different SOD1 mouse models were used to further understand the differences in progression of MND. Although these two mice had a mutation in the same MND-causing gene (SOD1), their genetic backgrounds differed as the mice were from different families.
This slight difference in other genes influenced the progression of MND and the mice exhibited two very different disease types (fast and slow progression) which the researchers then went on to study in detail.
A ‘shed’ load of data
The researchers looked specifically at the motor neurones in the two mice during the pre-symptomatic (before the onset of symptoms), symptomatic and end stages of the disease.
The researchers needed the genetic material, known as DNA or it’s reading template RNA, from inside the motor neurones to find out what changes occur in MND.
To identify these changes a microarray was used. This technique is used to screen an RNA sample for changes in 1000s of genes. These changes may be that a gene is ‘up’ or ‘down’ regulated. Up regulation means that a cell is following a specific gene to make a specific protein, which is a bit like following a recipe to make a specific type of cake. Whereas down regulation means that the cell is not following that particular recipe at that time (you only need a wedding cake for a wedding!).
Up and down genes
There was a real difference in the number of ‘up’ and ‘down’ regulated genes in the mouse with fast progression and the mouse with slow progression respectively.
In total the researchers found 2716 gene changes (either up or down) in the mouse with slow progression and 4063 in the fast progression model – a big difference considering they have the same SOD1 MND-causing gene!
Interestingly the researchers identified some key pathways and mechanisms that were down regulated in the mouse with fast progression. Impairment of mitochondrial function occurred, which we know is involved in MND, as well as protein transportation across the cell. It is thought that the build up of toxic proteins within the cell may be involved in MND and the cell being unable to transport new proteins seems to result in a fast progressive form of the disease.
In the slow disease progression model it was found that up regulation of immunological and anti-oxidant processes had neuroprotective effects in MND. The anti-oxidant process in particular would enable the cell to protect itself against oxidative damage (caused by free radicals) in MND. By targeting these particular pathways it may lead to the development of future treatments aimed at slowing disease progression in MND.
The research by Dr Bendotti and Prof Shaw has identified a number of key genes and pathways that affect the rate of progression of MND and why it varies from person to person. Having identified these pathways (eg mitochondrial function) we can potentially go on to develop future treatments aimed at slowing down the progression of MND.
Dr Bendotti said: “MND is a highly variable disease which makes assessment of potential treatments difficult. Thanks to the recent evidence in our laboratory and the successful collaboration with Prof Shaw and her team, we have identified some mechanisms that may help to predict the disease duration and eventually slow it down. I strongly believe that the new hypotheses generated by this study and our on going collaboration are the prerequisites to be able to fight this disease.”
Dr Brian Dickie, our Director of Research Development, added: “These new and important findings in mice open up the possibility for new treatment approaches in man. It is heartening to see such a productive collaboration between two of the leading MND research labs in Europe, combining their unique specialist knowledge and technical expertise in the fight against this devastating disease.”
Nardo, Giovanni, et al. “Transcriptomic indices of fast and slow disease progression in two mouse models of amyotrophic lateral sclerosis.” Brain (2013): doi:10.1093/brain/awt250