A recent study by Motor Neurone Disease Association-funded researcher Dr Tennore Ramesh from the Sheffield Institute for Translational Neuroscience (SITraN) has shown that even before the symptoms of MND occur, at the earliest stages of the disease, ‘connector neurones’ known as interneurons are already becoming damaged in the zebrafish.
Zebrafish are ideal models for helping scientists understand what happens in MND. Unlike mice and fly models, zebrafish have transparent embryos which enable scientists to get a unique view of the developing neurones under a microscope! Scientists can also look at disease progression in adult zebrafish by looking at muscle strength and measuring their progress swimming against a current.
Not only are zebrafish useful for helping scientists understand what happens in MND, they are also an ideal drug screening model. Zebrafish and humans are more similar than you may think (see Kelly’s post) and potential new MND drugs can be screened quickly. Looking at how MND progresses in the zebrafish, before symptoms appear, can help us gain a better understanding of what causes the disease.
Motorways, dual carriage ways and slip roads
No, I’m not writing about travel alerts or the latest road disruptions due to flooding or snow. In fact, these road systems happen to be a perfect example of what interneurons are, how they relate to motor neurones and what goes wrong in MND.
Our body consists of two types of motor neurones, which are known as upper and lower motor neurones. The upper motor neurones are found in the motor region of our brain and connect to the spinal cord. The lower motor neurones are found between the upper motor neurones in the spinal cord and connect to the muscles (e.g. in the arms and legs). Interneurons are the vital connections between the upper and lower motor neurones.
When a signal is sent from our brain to bend an arm it starts by travelling down an upper motor neurone. The signal then travels to a lower motor neurone via an interneuron. When the signal from the lower motor neurone reaches the muscle in our arm it causes the muscle to contract and bend.
In MND these upper and lower motor neurones become damaged and they are unable to transport the nerve signal from the brain to the muscle in our arm. This means we are unable to contract and bend, even though the brain is telling it to.
In our road system scenario the upper motor neurones are the motorways (e.g. the M1), and the lower motor neurones are the dual carriageways that link the motorways to nearby towns (e.g. the A38). In order for an upper motor neurone to send a signal (e.g. a car) to a lower motor neurone it needs to go via an interneuron, which in our road system scenario is a ‘slip road’ – making these interneurons vital connections between motor neurones.
This study has given us a better understanding of what happens in MND at the early stages of the disease (before symptoms occur). The researchers found that interneurons became damaged before the motor neurones themselves. Therefore this shows that interneurons are important in the early stages of the disease and scientists can begin to look at ways of preventing interneuron damage to see whether this has an effect on MND.
Adding more evidence to the puzzle
This study showed that, in zebrafish, interneurons are involved in the early stages of MND, which adds further evidence to previous work by another MND Association-funded researcher. Dr. Martin Turner (Oxford) also found damaged interneurons at the early stages of the disease before symptoms of MND occur in humans, with other studies showing interneuron damage in SOD1 mice models.
The next step would be to look at ways of preventing these interneurons from becoming damaged, to see whether this has any effect on the progression of MND.
This research is the first article we have paid to be made available Open Access, so that it is freely accessible to all. The article was published online in the prestigious journal ANNALS of Neurology on the 31 December 2012.
McGown, A. et al. Early Interneuron Dysfunction in ALS: Insights from a mutant sod1 Zebrafish Model. ANNALS of Neurology 2012 DOI: 10.1002/ana.23780 http://onlinelibrary.wiley.com/doi/10.1002/ana.23780/abstract