Analysis: while there are many suspects, no-one quite knows yet what causes motor neurons to die in motor neurone disease

By Bill Duddy and Stephanie Duguez, Ulster University

Motor neurons are cells in the brain which enable the brain to control your muscles. Without motor neurons, we become paralyzed, our muscle wastes away and we die. This is what happens in motor neurone disease, which is also known as Amyotrophic Lateral Sclerosis (ALS), a condition that has affected thousands of families in Ireland and millions world-wide.

But nobody knows what causes motor neurons to die in motor neurone disease. There are many suspects, both in terms of molecular changes inside neurons, but also toxic effects originating from other types of cell around the motor neurons, or toxins and pathogens in the environment, or some combination of these things. It's a molecular murder mystery for which the culprit has yet to be firmly identified.

Some clues come from studying genes – changes in the DNA sequences of certain genes are now known to cause more than 20% of cases of the disease. Over 30 such genes have been identified, and they influence various processes inside cells. If we imagine the cell as a factory, the DNA inside the cell is a book of instructions to make proteins. Proteins are molecular machines that make and break and otherwise manipulate all of the moving parts of the factory.

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The genes involved in motor neuron disease provide the instructions for proteins that carry out various different jobs. Some of these proteins form part of the mitochondria, which are the power generators of the factory – giant batteries that eat up food particles and oxygen to supply energy. Some affect communications in the factory, potentially interfering with the smooth running of the task, known as messenger RNA processing, by which DNA instructions are read and translated to make new protein machine parts. Others affect the conveyor belts and packaging facilities – the 'cytoskeleton' of long, winding protein filaments along which the molecular products of the factory are formed and processed. Yet others may affect the way in which molecular packages are prepared and sent from the factory.

But most cases of the disease remain unexplained. The processes affected by these genetic changes are basic cellular functions that take place in many cells and organs of the body and understanding them doesn’t necessarily help us to assign blame to any particular type of cell. In our molecular Whodunit investigation, these genetic changes hint at the murder weapon but not who wielded it.

The obvious place to start our investigation is the motor neuron itself. After years of research, the molecular changes that take place inside motor neurons in this disease are beginning to be understood – changes that include the ‘gluing up’ (aggregation) of certain proteins and a breakdown of some of the functions, like RNA processing, described above – but various studies suggest that the environment of the motor neuron is contributing to motor neuron death – that motor neuron death may not be initiated inside the cell itself.

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Historically, muscle has been regarded as a dependent in this story - an indirect secondary victim of motor neuron death. But muscle is not just a receiver of commands from the brain. Increasingly, it is recognised as a communicative organ in its own right. It secretes molecular messages such as growth factors and chemical signals, some of which enter general circulation in the bloodstream. These contribute to feedback loops between the muscle, liver, brain, and the immune system, all of which help regulate muscle size, diet, and general health of the body.

One way the muscle sends messages is by releasing particles called exosomes - these are tiny bag-like structures about 100 nanometres in size (one ten-thousandth of a millimetre). Despite these miniscule dimensions each exosome can carry hundreds of proteins, RNAs, and other molecules from one cell to another. If we imagine our cell factory to be stadium-sized, then a typical protein is roughly the size of a home printer, and an exosome can be thought of as a delivery truck filled with various types of proteins and other molecules.

We have been studying muscle stem cells taken from muscle biopsies of patients with MND and have found that certain aspects of the molecular make-up of these cells is very different from healthy muscle cells. Exosomes are much more abundant inside them, are released from them in greater quantities, and the contents of their exosomes are different. When we culture healthy motor neurons in the presence of muscle exosomes from MND patient cells, this kills the motor neurons. Muscle has previously been included in the list of suspects for MND, but a murder weapon could not be firmly established. We wonder if the muscle exosomes and their molecular contents may represent this murder weapon, offering new possibilities to treat, diagnose, and monitor the disease.

READ: Walking the walk: Fr Tony Coote and Motor Neurone Disease

In the course of this work, we have also found a way to extract muscle exosomes from blood samples. This method may ultimately help us to understand much better the role of muscle communication in health and disease, helping to develop new diagnostics and treatments for a range of health disorders. This could be important not only for neuromuscular, musculoskeletal and neurodegenerative diseases but also conditions such as diabetes, and the loss of muscle in cancer, and with ageing - conditions for many of which the molecular criminals are still at large.

Dr Bill Duddy is a lecturer in Stratified Medicine (Bioinformatics) in the School of Biomedical Sciences and a researcher with Biomedical Sciences Research at Ulster University. Dr Stephanie Duguez is a lecturer in Stratified Medicine (Musculoskeletal Health) and a researcher with Biomedical Sciences Research at Ulster University.

The views expressed here are those of the author and do not represent or reflect the views of RTÉ