Insights

MND Australia Research meeting 2013


Over 60 researchers gathered at Macquarie University for the Motor Neurone Disease Research Institute of Australia (MNDRIA) annual meeting held 18th November 2013.  The importance and purpose of the work about to be presented was crystallised by Chair of the MNDRIA Professor Dominic Rowe in his introduction. As we all known too well MND is a terrible and incurable disease leading invariably to death, Prof Rowe pointed out that it is only through the work of those in the audience, and colleagues around the world, that we will find a treatment or cure.  A single slide from Prof Rowe showed a frightening statistic; the number of deaths from MND, as a percentage of all deaths in Australia, had almost tripled in the last 15 years.

The meeting is a showcase of research that has been funded by MNDRIA over the past 12 months. Significantly, the work being conducted spans clinical electrophysiology, biomarker discovery, cognitive deficits, energy metabolism, genetics, and importantly cell and molecular biology of axon degeneration, protein homeostasis and protein degradation. Regardless of the explosion of genetic discoveries over the last few years, genetics remains a hot topic in MND research. In Australia there is still ~30% of inherited MND to be explained. The genetics work flow, and the discovery of a new MND/ALS gene was described by Professor Ian Blair and his postdoctoral researchers Dr Kelly Williams and Dr Shu Yang, Macquarie University. The identity of the gene is not yet published, but hints were given as to the pathways it might contribute to. Prof Blair described how many of the MND causing genes can now be functionally categorised in to either RNA metabolism (TDP-43, FUS, TAF15, EWSR1) or protein degradation pathways (UBQLN2, VCP, p62). The Blair group spoke at length about a new genetic discovery that falls within in the protein degradation pathways and argue that this discovery adds more weight to the argument that protein degradation pathways are dysfunctional in MND.

The dying forward and dying back debate continued to rage on during the meeting with Dr Parvathi Menon, University of Sydney, presenting work suggesting that cortical hyperexcitability may explain split-hand symptom of MND. Adding to this was Dr Neil Simon, Neuroscience Research Australia, who presented work suggesting that upper motor neuron involvement may be clinically assessed by H-reflex measurements. In rodents both Dr Anna King, University of Tasmania, and Dr Catherine Blizzard, University of Tasmania, presented evidence that excitotoxicity causes a dying back phenotype and that this effect is only seen when the toxin is presented to cell bodies, consistent with a dying back mechanism. Importantly, Dr King presented data that showed that treating with the anti-cancer drug taxol that stabilises microtubules prevented this toxin induced die back.

The topic of biomarkers was also a popular one, with a number of talks around the discovery and use of biomarkers. This area has obvious and important clinical and eventually treatment consequences. pNFH was put forward as a biomarker by Dr Rob Henderson, University of Queensland, but it was pointed out that there is a large subpopulation of patients for which this is not a robust measure. Dr Henderson presented work to suggest that measuring motor unit number was still an accurate measure of disease progression, but this is not a viable marker available for long term use.  Interestingly, a much less invasive marker was suggested by Dr Mary-Louise Rogers, Flinders University.  The extracellular domain of p75 receptor was found in urine of both MND mice and patients suggesting that this may be a useful marker for disease.

While genetic discoveries are increasing our list of known causes of MND, the actual mechanism that causes motor neurone death resulting from the discovered mutations are still to be determined. Protein homeostasis is the concept that the proteome must be maintained in the correct 3D structure, at the appropriate concentrations and in the desired location in the cell to be functional. Much work is being conducted around the inappropriate accumulation of MND associated proteins in various regions of the cell or even outside cells. The most common example of which is the cytosolic accumulation of TDP-43. Dr Diane Moujalled, University of Melbourne, presented work that indicated that C-Jun N terminal kinase controls TDP-43 accumulation in stress granules. However, whether the formation of stress granules is favourable or detrimental is yet to be determined. In addition, while SOD1 is normally a cytosolic protein, it can be found outside cells, Dr Julie Atkin, La Trobe University presented work to show that SOD1 outside of cells could be taken up by neurons and that this uptake of aggregated SOD1 activates the unfolded protein response, inhibits ER-Golgi transport and promotes golgi fragmentation. Continuing on with SOD1, Dr Brad Turner, University of Melbourne, presented his work demonstrating that expression of mutant SOD1 produced enlarged endosomes. This correlated with an increase in endosome markers Rab5 and Rab11 in cells and in MND patients. Collectively the work presented would suggest that modifying protein homeostasis pathways may be an effective treatment strategy for MND.

The meeting finished with a great poster session that touched on topics as diverse as end of life issues, diagnostic utility of threshold tracking TMS, stress granule formation, T-cell involvement in disease progression and the misincorporation of the toxin BMAA into human proteins just to name a few.

The MND/ALS research community in Australia has grown substantially in the last 5 years and with it the MNDRIA meeting has gone from a small room in Gladesville and around 20 researchers and an afternoon of talks, to a 100 seat auditorium filled with researchers listening to a full day of talks followed by a poster session. To top this off the MNDRIA announced more than $2.2 million in funding for ALS/MND in 2014. It was clear by the end of the day that we are gaining momentum in the fight against MND.

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