This was my first time at the MNDA symposium and I was excited at the thought of getting to put faces to names of those whose papers I have read! On arriving at the conference centre on the first day in Brussels I was amazed at the number of people who had travelled from all over the world to attend the symposium.
During the introductory talks, the significance of the Ice Bucket Challenge to MND research was discussed and the implication it had upon those working on ALS/MND. Having taken part in SITraN’s ice bucket challenge back in September it was inspiring to see the total amount of money that had been raised worldwide as a result of the campaign.
I am reporting about the third scientific session entitled protein misfolding and toxicity. The first talk from this session was by Mikael Oliveberg from the Department of Biochemistry and Biophysics at Stockholm University, Sweden. Oliveberg talked about the dynamics of protein misfolding in particular how pathologic aggregation in mice expressing human SOD1G93A mimics the behaviour of the mutant SOD1 protein in a test tube. He showed that in vivo protein aggregation obeys simplistic physical-chemical rules, predicted from causative protein properties in vitro and that the same exponential growth is seen in the spinal cord of SOD1G93A mice using dot blot analysis and an antibody to unfolded form. The talk concluded with a discussion about the cause of the spread of aggregation and whether the ‘load’ of misfolded protein could play a role in death, due to observations that all mice in the terminal stage have very high levels of misfolded SOD1 proteins (exponential misfolding in a test-tube).
The next talk was about the propagation of the misfolding-competent by Edward Pokrishevsky from the University of British Columbia, Canada. He showed that mutant FUS or TDP-43-induced misSOD1 can spread intercellularly through conditioned media triggering misfolding of endogenous wtSOD1 in untransfected cells. Cells with knockdown of SOD1 by siRNA contained no misfolded SOD1, suggesting that endogeneous SOD1 is required for active conversion. Immunodepletion of misSOD1 from conditioned media using antibodies specific for misfolded SOD1 prevented the spread of SOD1 misfolding. Pokrishevsky also showed that the absence TDP-43 pathology in cells with SOD1 misfolding, suggests that misfolding SOD1 can occur independently of TDP-43. This talk highlighted the use of misfolding-specific antibodies and their potential as a therapeutic.
Next to talk was E Tokuda from the Department of Medical Bioscience, Sweden about co-expression of strain A- and B-aggregate forming human SOD1 mutants in in mice. He showed that disease can be modulated by combining two hSOD1 mutants – crossing hemizygous hSOD1G85R with hemizygous hSOD1G90A. The characterization of these mice is now underway.
The final talk of this session came from Nobuto Shibata from the Department of Pathology in Tokyo, Japan. He was working on understanding glutamate stimulation in motor neurons and their ability to form p-TDP-43 aggregates. Shibata provided in vitro evidence that glutamate stimulates motor neurons to form p-TDP-43 aggregates via the MEK pathway.
This is my summary of just one of many exciting scientific sessions from the MNDA Symposium 2014. I have returned from the meeting with a refreshed knowledge of current MND research and lots of exciting new ideas for my own work. And despite a research filled few days, it was impossible not to pick up some festive spirit from the beautiful light show at the Grand Place and Brussels’ streets, which were filled with Christmas lights and markets!