Are we closer to understanding the underlying causes of MND?
Professor Justin Yerbury from the Illawarra Health and Medical Research Institute (IHMRI) and UOW’s School of Chemistry and Molecular Bioscience has spent the last decade trying to understand the underlying cause of MND.
His investigations have been published in one of the leading neuroscience journals, Trends in Neurosciences.
Professor Yerbury, with his colleagues Dr. Luke McAlary and Senior Research Assistant Natalie Farrawell, has taken a detailed look at research into what causes the breakdown of motor neurons leading to MND.
Professor Yerbury explains part of his research:
Why are motor neurons at risk of dying in neurodegenerative diseases like MND and ALS?
We think it has to do with the unique combination of proteins in motor neurons.
Our analysis has identified the cells that die in MND are particularly at risk because their proteins are supersaturated. This means that there are so many more protein molecules in the solution than what we might expect. Supersaturation is a word used more generally to mean that a solution has more of a substance in it than possible under normal circumstances. This means that if conditions change, the substance is at risk of crashing out of solution.
So what kinds of things can trigger protein imbalance in motor neurons?
We know that approximately five to 10 per cent of all cases of MND are inherited and caused by faulty genes. Natalie Farrawell’s experiments have shown that even one small mutation in specific genes is enough to cause protein deposits to form.
The remaining 90 per cent of cases are random or sporadic in the population. There is no consensus on what the underlying cause of these cases are.
Two intriguing possibilities are a toxin from blue green algae and reactivation of ancient endogenous retrovirus in our genes. The toxin works its way into proteins which makes them change shape and malfunction. The activation of dormant viruses our ancestors acquired millions of years ago would put pressure on the cells systems that control protein production and degradation, allowing protein deposits to form.
While some cases may be associated with these factors, there is still much work to understand the disease trigger in sporadic MND.
What we have found
When aggregates do form, one motor neuron response is to slow down the production of the proteins that are at most risk: the ones that are supersaturated.
By making less of the at risk proteins, neurons can make sure that there are less proteins aggregating.
In motor neurons, some of the most at risk proteins are in charge of controlling electrical signals. They do this by moving charged molecules across the boundary of the neuron. By slowing down the production of all proteins at risk, this means that many of the proteins that control electrical signals are reduced.
This reduction leads to the motor neurons not firing properly, can result in messages not getting through to our muscles.
Our work suggests that genetic mutations that cause MND tips the fine balance, resulting in the deposition of supersaturated proteins in motor neurons. Motor neurons respond by turning down at risk, proteins including those important for electrical signals.
Now that we have gained a little insight into what is happening in motor neurons, we have started to think about ways that we can restore the protein balance.
One thing we are trying to discover now is ways to restore the protein balance by removing the proteins that are accumulating.
Professor Yerbury was diagnosed with MND in 2016.
Louise Negline, Communications Coordinator
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