University of Tasmania, Australia

Aberrant excitatory activity (excitotoxicity) is implicated in a number of neurodegenerative diseases of the nervous system including AD, ALS, MS and following CNS injury. Our studies have demonstrated that excitotoxicity can lead directly to axonal injury, which is an important pathological finding in these diseases. Axonal protection from excitotoxicity has been ignored therapeutically, despite studies indicating that axon degeneration occurs as an independent mechanism from cell death. Axonal protection may provide better functional outcomes in disease when used alone or in combination with agents that protect against cell death.

The aim of this study is to investigate the mechanism of axonal degeneration following excitotoxicity in both in vitro and in vivo models and identify points of therapeutic intervention. For these studies we are using the microfluidic compartmented chamber platform, a novel cell culture technique, to separated the axonal compartment from the somatodendritic compartment, allowing us to probe axon degeneration mechanisms pharmacologically. We are combining these techniques with time lapse live cell imaging to probe these mechanisms in real time. Our studies demonstrate that microtubule destabilization is an early pathological alteration in excitotoxin induced axon degeneration, occurring upstream of protease activation and resulting in axonal fragmentation. We propose that microtubules play a central and upstream role in orchestrating the pathological series of changes in excitotoxin induced axon degeneration. Outcomes (Potential or realized): To determine points of intervention and test the therapeutic potential of drugs that rescue the axon from degeneration.