Axon transport as a target for promoting RGC survival and optic nerve regeneration

Abstract

AbstractAdult CNS neurons have a weak intrinsic capacity for regeneration after injury, but the underlying cellular mechanisms preventing regeneration are not completely understood. Increasing intrinsic growth ability is a critical part of enabling injured optic nerve axons to regenerate. The work presented here is part of a large body of research into understanding the role of membrane protein trafficking and transport in the control of regenerative ability. We have found that as CNS neurons mature, there is a developmental decline in the axonal transport of integrins (cell surface adhesion and guidance molecules) and their endosomal transporters, Rab11 positive recycling endosomes. This is controlled by a molecular switch called ARF6. Switching off ARF6 in mature CNS axons leads to an increase in the anterograde axonal transport of integrins and Rab11 endosomes, leading to a restoration of the regenerative capacity that is lost as axons mature. We have been targeting these mechanisms to stimulate axon regeneration in the optic nerve, and neuroprotection of retinal ganglion neurons during raised IOP. Here we present novel data from two new lines of investigation into facilitating CNS axonal transport, neuroprotection and regeneration, focusing on signaling pathways and organelle motility. Firstly, by investigating signaling upstream of ARF6, we have identified an isoform of PI3 Kinase which we have used to stimulate axon transport, neuroprotection and regeneration; both after laser axotomy in vitro and after optic nerve crush. Secondly, we present exciting new data from studies into a trafficking molecule which resides in the endoplasmic reticulum (ER) and demonstrate that this can be targeted to enable robust optic nerve regeneration and neuroprotection in the retina. These findings confirm integrins and Rab11 as critical facilitators of optic nerve regeneration whilst establishing an important new role for the axonal ER in this process.