Motor Neurone Disease: New Insight about how it works

When we imagine how research results can change society or help us make new bounds in medical science we think of proving a hypothesis or cracking a code, but sometimes research that refutes a theory can be just as beneficial, as scientists can eliminate a hypothesis from the mix and save years of wasted-time investigating dead ends and a team of German researchers has just done exactly that.

Writing in the journal Proceedings of the National Academy of Sciences (PNAS), the team refute a widely accepted hypothesis about a causative step in neuro-degenerative conditions.

These results deal specifically with animal models of human amyotrophic lateral sclerosis (ALS), more commonly known as Motor Neurone Disease, but the findings also have implications for other neuro-degenerative diseases such as Alzheimer's or Huntington's disease.

One of the ways neuro-degenerative diseases manifest themselves is in the loss of axons - essentially, the transmission lines for electrical signals in individual nerve cells - and synapses, the key sites for communication between them.

In the past, such damage has been attributed to deficits in the bi-directional transport of organelles, such as the intracellular power plants called mitochondria, along the axons of nerve cells.

The team, from the Technische Universitaet Muenchen (TUM) and Ludwig-Maximilians-Universitaet Muenchen (LMU), put these previously-held assumptions to the test in one of the most thorough tests carried out to date.

They used novel imaging techniques, with high resolution in both space and time, to observe changes in both axon morphology and organelle transport in several different animal models of ALS.

Their results show that transport deficits and axon degeneration can develop independently of each other, throwing into question the theory that one is a direct cause of the other.

They observed axonal organelle transport in living tissue in real time, and in a way that enabled them to track the movement of individual mitochondria, using a novel imaging approach that involves transgenic labelling.

They were also able to observe transport of another kind of organelle, endosome-derived vesicles. Several different animal models of ALS were investigated, all of which are based on human mutations associated with the disease.

One of the study authors, Professor Thomas Misgeld from the Institute of Neuroscience at the Technische Universitaet Muenchen, comments on their findings: 'We do think these insights have implications for other studies of ALS, or even studies of other neuro-degenerative diseases.

What our experiments really say is that it is not easy to develop faithful models of neuro-degenerative diseases.

So it might be worth spending more effort to get better animal models, as this is the only way forward for mechanistic studies, while always checking them against human pathology or human-derived cellular models.

In the meantime, it is probably prudent to work with several of the available models in parallel. Moreover, in more general biological terms, our results also speak to the relationship between axonal transport disruptions and degeneration - which might not be as tight as we assumed. Here we have a lot more to understand.'

The iPSoALS project brings together researchers from France, Germany, Israel and Sweden with the aim of better understanding ALS disease mechanisms.

For more information, please visit: Technische Universitaet Muenchen (TUM)