Abstract
The development of neuroprotective treatments is urgently needed for neurodegenerative and neurotraumatic diseases. As axonal degeneration is a key initiating event in these diseases, it is pivotal to better understand and counteract axonal degeneration. A traumatic lesion of axons in the central nervous system is followed by acute axonal degeneration (AAD) within several hours. However, the underlying molecular mechanisms of AAD are still incompletely understood. The aim of this study was to investigate the mechanisms of AAD following calcium influx after optic nerve crush in vivo and after axotomy of cortical neurons in the microfluidic chamber system in vitro. A continuous increase in calpain activity was demonstrated following calcium influx. Calpain then cleaved collapsin response mediator protein (CRMP2), which impaired mitochondrial transport. Both calpain inhibition and CRMP2 overexpression almost completely inhibited axonal fragmentation proximal to the lesion site during AAD. Finally, several CRMP2-interacting partners were regulated during AAD and might contribute to AAD.
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