In a study published in Nature Neuroscience this week, a collaboration led by Dr. Jemeen Sreedharan and colleagues from King’s College London, the Babraham Institute and the University of Cambridge have published a new mouse model of Motor Neurone Disease (MND).
The study takes advantage of cutting edge gene editing technology called CRISPR/CAS9 to generate a mouse model of the human disease that accurately mimics a genetic component found in some people affected by MND. The researchers used the gene editing technology to precisely change (mutate) the gene that the body uses to produce the protein TDP-43, a very important player in the MND story implicated in almost all cases of MND.
The genetic change induced by the team in this study has been shown to occur in people with MND and is highly toxic in many laboratory experiments both in vitro (cells in a Petri dish) and in vivo (in living laboratory animals, including, flies, worms and fish). Dr. Jemeen Sreedharan, the principal investigator, and colleagues introduced the mutation in the exact same position in the gene of the mouse, as it is found in some humans with this genetic cause of MND.
In this mouse, the TDP-43 mutation results in the protein losing its ability to self-regulate, and so the protein levels become higher than normal. This caused a chain reaction that changes to the levels of several other proteins highlighting genes which TDP-43 also normally controls. Interestingly, one of the genes was a gene that encodes “Tau” (rhymes with wow) which is a protein that is associated with Alzheimer’s disease. Perhaps as a result some of the mice had frontotemporal dementia like cognitive changes, just as occurs in around 15% of people affected by MND.
However, it is well known that if you have a mutation in a gene known to cause MND, this does not necessarily mean that you will develop the disease. This has even been shown with identical twins who have the same genes, where one may develop disease and the other never develops symptoms in their lifetime. In addition, the age at which a person will first get symptoms and the severity of the disease can vary considerably between people. It is assumed that some genetic variation and interaction with environment influences this difference in onset and degree of severity of symptoms between individuals.
Just as in humans, only some but not all of the mice in the study with the CRISPR/Cas9 genetic mutation in TDP-43 did show major symptoms. This suggests that some of the mice were resistant to the neurodegeneration whilst others were susceptible. Indicating that other factors within the animals’ biology were at work to protect the unaffected mice from disease. This is a surprising finding since the mice are bred to be as genetically identical as possible and were being kept in the same environmental conditions.
This lack of symptoms in some of mice could have been viewed as a disappointment by the researchers (they were trying to make mice with MND), but in fact it is a good reflection of the range of symptom severity and disease onset seen in the human disease (Just like the identical twins case). The research team turned this to their advantage in order to learn more about the mechanisms that underlie the disease and potential mechanism of neuro protection occurring in the mice.
They split the mice into two groups, those with symptoms and those without, and analysed the genes that were differently activated between the two groups. These mice which do not develop symptoms of disease, just like some people, are perhaps dealt a ‘good hand’ which during their lifetime contains ‘good genes and factors’ that offer protection from the bad ones. By comparing the biology of those mice or people who are resistant to disease with those who show symptoms, they are able to identify modifiers or protective genes. This gives us the opportunity to understand why some people appear to be resistant to disease, or live longer than others.
Identifying affected genes
By comparing the differences in the active genes between the disease resistant mice and those showing disease symptoms the research team identified a number of key changes between the groups. There was a difference in the activity of over 450 genes between the mice without symptoms and those with, that are involved in the mechanism of the disease, and more importantly are associated with protection against symptoms. By identifying these 450 genes, the team are uncovering key targets that offer the potential new avenues for development of therapeutics and further understanding the underlying causes of MND.
Some of these were genes already known to be important in MND and the health of neurons, providing confidence in the findings. These outcomes provide new avenues in our understanding of the mechanisms at work in both FTD and MND, a disease which currently has no cure or effective treatment, little understanding of the cause and a lifetime risk of 1 in 350. We are delighted to see the outcomes of this MND Association supported work which moves us another step closer to our vision of a world free from MND.
Listen to Dr. Jemeen Sreedharan talk about this work here in a Naked Scientist Special Podcast (7mins)