It is thought that a number of genetic, environmental and lifestyle factors combine before most forms of MND develop. While researchers are still trying to identify what these environmental and lifestyle factors might be, they have made huge steps forward in our understanding of the gene changes behind MND. To read more about what a gene is, please see our previous blog on DNA.
What do we mean by gene changes?
Our genes act like instructions to build and maintain the cells within our body. Changes can happen to genes, a bit like how there can be changes to an instruction manual. The majority of changes will go unnoticed and will not affect the outcome of the instructions. However, some changes cause the instructions to be very different and the final product does not work how it should.
If we take the example of baking a cake, the original instructions state:
Add butter and sugar to the bowl and cream together.
Now if we make a small change to the instructions:
Add sugar and butter to the bowl and cream together.
This small change will not have an impact on the final cake and will still taste great. However, if we make a major change to the instructions:
Add salt and butter to the bowl and cream together.
Swapping the sugar for salt will have a big impact on the final cake. It won’t taste very sweet and probably won’t work as a dessert anymore.
Changes to some genes have been linked to why motor neurons can become damaged and die. Anyone with MND who has changes in genes which are linked to the disease has ‘genetic MND’.
How do gene changes happen?
We have two copies of genetic instructions of each gene; one copy comes from each biological parent. This means that we inherit 50% of our genes from each biological parent. Changes to genes can be passed down, or inherited, from biological parents to children.
Around 10% (one in ten) of people with MND have inherited MND (also known as familial MND). This means they have inherited a gene change that is linked to the disease from their biological parents. Inherited MND nearly always follows what is known as a ‘dominant inheritance pattern’. This means that it only takes one changed copy of the gene to increase someone’s risk of developing the disease. In most cases, a person with a gene change linked to MND has one biological parent who also has the gene change. Therefore, a child will have a 50% chance of inheriting the change from the biological parent. You can read more about inherited MND in a booklet on our website.
It is important to note that while inheriting a gene change linked to MND does increase risk of getting the disease, it does not mean a person will definitely develop MND.
This is known as ‘reduced penetrance’. Penetrance describes the proportion of people with a gene change who develop the disease. Some people who have the gene change might not develop MND. This is why someone may have a biological grandparent who developed the disease but their biological parents didn’t.
MND has reduced penetrance because it is thought that genetic changes alone do not cause the disease. Instead, it is suggested that a number of genetic, environmental and lifestyle factors accumulate during our lives and need to combine before most forms of MND develop.
The majority (90%) of people with MND do not have a family history of the disease. This type of MND is described as sporadic. Researchers have also found changes in genes linked to MND in some people with sporadic MND. It is thought that these gene changes may happen during a person’s lifetime, potentially due to lifestyle or exposures to different environmental factors. The exact factors and reasons why these changes happen are not yet known.
You can read more about the lifestyle and environmental factors that have been investigated as potential risk factors of MND in our previous blog.
4 Most Commonly Changed Genes In MND
Since 1993, changes in over 40 genes have been linked to the development of MND and, while we understand the effects of some of these, there is still a lot to uncover about how some changes affect the cells.
The 4 most common genes that have changes linked to MND are C9orf72, SOD1, FUS and TARDBP. These genes play crucial roles in keeping neurons healthy and changes in these genes have been well studied by researchers to uncover how they are linked to MND. When changes happen in these genes, they contribute to damage and ultimately the death of motor neurons.
C9ORF72 gene
The most common gene change in MND is in the C9orf72 gene. Within our genes, there is a genetic sequence, like the letters that make up words allowing you to read. In the C9orf72 gene there are normally some repeat sequences, the same way the word ‘letter’ has double ‘t’. In healthy people there can be up to 30 repeats of this sequence. When people with MND have this gene change, the sequence may have up to 1400 repeats, like a song stuck on repeat. This extra repeating sequence is known as a ‘repeat expansion’ as the repeating sequence expands the length of the genetic instructions.
It is still not fully understood how the C9orf72 gene change damages motor neurons, but researchers have several different theories. It is thought that the C9orf72 gene change causes:
- The formation of toxic clumps of proteins in the cells which damage the cell.
- The protein stops functioning as it should, allowing toxins to build up inside the cell.
- Impacts other complex processes within the cell, which stop the cell from working properly.
Some people with this gene change may also develop a form of dementia known as frontotemporal dementia (FTD). Research has provided increasing evidence that MND and FTD are connected, with changes in the C9orf72 gene also being found in 40% of people with FTD. FTD is a group of disorders where the nerve cells in two areas (frontal lobe and temporal lobe) in the brain are damaged. In a similar way to how motor neurons break down in MND and cause loss of functions to muscles, the damage to nerve cells in FTD causes the connections between parts of the brain to break down. As more cells become damaged and die this can lead to symptoms such as problems with memory, thinking or language, changes in mood, emotions and behaviour.
SOD1 gene
Changes in the SOD1 gene are the next most common genetic form and account for 2% of all people with MND. The SOD1 gene is used to make the SOD1 protein which normally protects cells such as neurons and muscles from harmful toxins building up within the cell. The SOD1 protein ensures these toxins are cleared away and keeps the cells healthy. Much like a snow plough would clear the roads on a snowy day, stopping people getting stuck and preventing traffic jams and accidents.
If the SOD1 gene is changed, this protein becomes faulty and can no longer clear away toxins, so they begin to pile up. When these toxins pile up, with no way to clear them, the cell will become stressed similar to if you were snowed in at home.
Additionally, the faulty SOD1 protein clump together within the neurons, blocking healthy cell functions. If the toxins and faulty SOD1 clumps are not cleared, cells will run out of energy and oxygen causing them to die.
TARDBP gene (TDP-43 protein)
TARDBP gene changes are quite rare and only affect around 4% of people with genetic MND. The TARDBP gene is used to make a protein called TDP-43 which plays many important roles within our cells. The TDP-43 protein is usually found in the nucleus (control centre) of the cells and this is where it helps to control the activity of other genes and the production of other proteins.
In MND, the TDP-43 protein leaves the nucleus of the cell, where it carries it out it’s job, and enters the cytoplasm. It can’t work as it should here and joins together to form clumps which become toxic to the cell as they interfere with the normal processes and cause stress for the cell.
The TDP-43 protein is usually found in the nucleus of the cell but in MND, it moves outside of the nucleus into the cytoplasm and forms clumps which are toxic and damage cells.
FUS gene
FUS is a very rare form of MND which can occur in children and adults. This form of the disease is usually highly aggressive and can progress extremely quickly. Normally the FUS gene produces the FUS protein which stays in the nucleus of the cell, the control centre containing the DNA. This protein helps make other proteins and repair damage to the DNA to keep the cell healthy.
In FUS-MND, the FUS gene is changed and forms an abnormal FUS protein. This abnormal protein is able to move out of the nucleus into the cytoplasm of the cell and form toxic clumps. The build-up of toxic clumps within the motor neurons stops the cell from working effectively and can cause stress to the neuron resulting in it dying.
There is still much to uncover about the gene changes that are linked to MND and how they may contribute to damaging the motor neurons. We still don’t know everything about the 4 most commonly changed genes in MND but we know some of the ways in which the cell is damaged as a result of them. If we can understand more about how gene changes contribute to MND, effective therapies could be designed to target the gene changes and stop or reverse these effects. Gene therapies could hold the key for effective treatments of MND for people who have specific gene changes.
The genes and proteins involved in genetic MND can be measured to give an indication of disease progression and activity. Using gene and protein activity as markers of disease may help in diagnosis, more accurately predicting someone’s disease progression and determining if a potential treatment is effective. You can find out more about markers of disease in the next blog.
