Adult mammalian central nervous system axons have intrinsically poor regenerative capacity, so axonal injury has permanent consequences. One approach to enhancing regeneration is to increase the axonal supply of growth molecules and organelles. We achieved this by expressing the adaptor molecule Protrudin which is normally found at low levels in non-regenerative neurons. Elevated Protrudin expression enabled robust central nervous system regeneration both in vitro in primary cortical neurons and in vivo in the injured adult optic nerve. Protrudin overexpression facilitated the accumulation of endoplasmic reticulum, integrins and Rab11 endosomes in the distal axon, whilst removing Protrudin's endoplasmic reticulum localization, kinesin-binding or phosphoinositide-binding properties abrogated the regenerative effects. These results demonstrate that Protrudin promotes regeneration by functioning as a scaffold to link axonal organelles, motors and membranes, establishing important roles for these cellular components in mediating regeneration in the adult central nervous system.

Cambridge Institute for Medical Research and Department of Medical Genetics University of Cambridge Cambridge UK

Centre for Eye Research Australia Royal Victorian Eye and Ear Hospital Melbourne Australia

Centre for Reconstructive Neuroscience Institute of Experimental Medicine CAS Prague Czech Republic

Department of Clinical Neuroscience Division of Eye and Vision St Erik Eye Hospital Karolinska Institutet Stockholm Sweden

Department of Ophthalmology Addenbrooke's Hospital Cambridge UK

John van Geest Centre for Brain Repair Department of Clinical Neurosciences University of Cambridge Cambridge UK

Laboratory of Developmental Neurobiology Division of Intramural Research National Heart Lung and Blood Institute NIH Bethesda USA

MRC Mitochondrial Biology Unit University of Cambridge Cambridge UK

Ophthalmology Department of Surgery University of Melbourne Melbourne Australia

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