Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS

Author(s): Veselina Petrova (1), Craig S Pearson (2), Jared Ching (3,4,5), James R Tribble (6), Andrea G Solano (2), Yunfei Yang (5), Fiona M Love (3), Robert J Watt (3), Andrew Osborne (3), Evan Reid (7), Pete A Williams (6), Keith R Martin (3,8,9), Herbert M Geller (2), Richard Eva (10), James W Fawcett (11,12)

1 John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. vp351@cam.ac.uk.
2 Laboratory of Developmental Neurobiology, Division of Intramural Research, National Heart, Lung and Blood Institute, NIH, Bethesda, USA.
3 John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
4 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
5 Department of Ophthalmology, Addenbrooke's Hospital, Cambridge, UK.
6 Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
7 Cambridge Institute for Medical Research and Department of Medical Genetics, University of Cambridge, Cambridge, UK.
8 Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Australia.
9 Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
10 John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. re263@cam.ac.uk.
11 John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. jf108@cam.ac.uk.
12 Centre for Reconstructive Neuroscience, Institute of Experimental Medicine CAS, Prague, Czech Republic. jf108@cam.ac.uk.

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.

Nat Commun. 2020 Nov 5;11(1):5614. doi: 10.1038/s41467-020-19436-y.

PMID: 33154382

Experimental Paper of the Month manager: Anthony Khawaja
Editorial Board: Humma Shahid, Karl Mercieca, Francisco Goni
Editors in Chief: Francesco Oddone, Manuele Michelessi