On 3 March 2014, researchers based at the University of Edinburgh published a research paper that extends our understanding of the childhood disease – Spinal Muscular Atrophy (SMA).
Although this is not MND so-to-speak, the disease does affect the motor neurones. Plus, the results were so interesting; I couldn’t resist writing a blog post about them.
Floppy baby syndrome
SMA is a childhood disease of the motor neurones and is sometimes known as ‘floppy baby syndrome’. It affects 1 in 6,000 births making it more common than MND, which affects approximately 1 in 100,000 people.
Unlike MND, where only 5-10% of cases are caused by a genetic mistake (known as inherited MND), SMA is known as an autosomal recessive genetic disease.
An autosomal recessive genetic disease is different to an autosomal dominant genetic disease (as seen in most cases of inherited MND).
In autosomal dominant disease an individual only needs to inherit one disease causing gene to develop the disease. Whereas, in an autosomal recessive disease, an individual needs to inherit two copies of the disease causing gene (one from each parent).
This means that two parents could be unaware that they are carriers of the disease causing gene (because they have one disease causing gene and one healthy gene). It is only when they go on to have a child that there is a chance they could inherit both copies of the genes and develop the disease.
Unlike MND, the cause of SMA is known. Researchers have identified that the disease is caused by a mutation in the Survival Motor Neurone (SMN) gene. Mutations in this gene are not associated with MND, however, the way in which this mutation causes SMA has been somewhat elusive. Only now have researchers at the University of Edinburgh been able to shine a light on how this gene causes SMA.
The mutation in the SMN gene causes the cells to no longer produce enough of the SMN protein and the researchers have identified that this decrease in SMN also causes a decrease in a key enzyme known as UBa1.
UBa1 is a key component of the Ubiquitin pathway. The Ubiquitin pathway is the recycling team within the cell. If the recycling team goes on strike, this causes an increase in un-recycled proteins – causing an unhealthy ‘mess’ within the motor neurones.
In SMA, the inability of the recycling team to get rid of these proteins leads to a build up of a protein known as B-catenin. The control centre of the cell (the nucleus) is unaware that its recycling team are on strike. This causes the cell to continually make new B-catenin leading to a build-up within the cell
By studying SMA in mice, fruit flies and zebrafish the researchers have shown that the gene is conserved across species. This means that what happens in these animal models is also likely to occur in humans.
As well as furthering our understanding, the researchers identified that if they blocked the cell from making new B-catenin they could improve the symptoms of SMA in mice, fruit flies and zebrafish.
By using a plant derived pigment known as ‘Quercetin’, the researchers found that the compound was able to block the motor neurones from making new B-catenin proteins. This caused improved performance and symptoms in all three animal models.
However, Quercetin did not increase body weight or survival – indicating that other mechanisms are involved in the disease. Through further study, the researchers went on to discover that B-catenin was only present in high amounts within the motor neurones, and not other cells which become affected in the later stages of the disease.
What it all means?
The researchers at the University of Edinburgh have vastly increased our knowledge on SMA, and how the mutation in the SMN gene causes disease. Not only this, the researchers have shown that they can pharmacologically target B-catenin signalling in animal models to improve symptoms early on in the disease.
The reason these results are interesting in MND is because in 2011 researchers identified the Ubiquilin 2 gene as a cause of some cases of inherited MND. The protein from this gene was also found to be ‘clumped’ within the motor neurones in the majority of cases of MND (not caused by a gene mutation).
Ubiquilin 2, like Uba1, is also involved in the ubiquitin recycling team. This research from the University of Edinburgh suggests that further study of this pathway is important in enhancing our understanding of neurodegenerative disease.
Dr Brian Dickie, Director of Research Development at the Association, commented: “The cell’s recycling system – the ability of the cell to get rid of defective proteins – goes wrong in MND. This breakdown of communication between making new proteins and getting rid of old ones is a key area of neurodegenerative disease research.
“If we can find out why this happens in one neurodegenerative disease, like SMA, it can help steer our understanding to finding out why this happens in other neurodegenerative disease, including MND.”