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Brain Advance Access originally published online on August 29, 2008
Brain 2008 131(10):2606-2619; doi:10.1093/brain/awn196
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

BAG1 promotes axonal outgrowth and regeneration in vivo via Raf-1 and reduction of ROCK activity

Véronique Planchamp1,2, Christina Bermel1, Lars Tönges1, Thomas Ostendorf1, Sebastian Kügler1,3, John C. Reed4, Pawel Kermer1,3, Mathias Bähr1,3 and Paul Lingor1,3

1Department of Neurology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, 2European Research Training Network (RTN) ‘Nervous System Repair’, 3DFG-Research Center for Molecular Physiology of the Brain (CMPB), Göttingen, Germany and 4Burnham Institute for Medical Research, La Jolla, California 92037, USA

Correspondence to: Dr Paul Lingor, Department of Neurology, University Medicine Göttingen, Germany. E-mail: plingor{at}gwdg.de

Improved survival of injured neurons and the inhibition of repulsive environmental signalling are prerequisites for functional regeneration. BAG1 (Bcl-2-associated athanogene-1) is an Hsp70/Hsc70-binding protein, which has been shown to suppress apoptosis and enhance neuronal differentiation. We investigated BAG1 as a therapeutic molecule in the lesioned visual system in vivo. Using an adeno-associated viral vector, BAG1 (AAV.BAG1) was expressed in retinal ganglion cells (RGC) and then tested in models of optic nerve axotomy and optic nerve crush. BAG1 significantly increased RGC survival as compared to adeno-associated viral vector enhanced green fluorescent protein (AAV.EGFP) treated controls and this was independently confirmed in transgenic mice over-expressing BAG1 in neurons. The numbers and lengths of regenerating axons after optic nerve crush were also significantly increased in the AAV.BAG1 group. In pRGC cultures, BAG1-over-expression resulted in a ~3-fold increase in neurite length and growth cone surface. Interestingly, BAG1 induced an intracellular translocation of Raf-1 and ROCK2 and ROCK activity was decreased in a Raf-1-dependent manner by BAG1-over-expression. In summary, we show that BAG1 acts in a dual role by inhibition of lesion-induced apoptosis and interaction with the inhibitory ROCK signalling cascade. BAG1 is therefore a promising molecule to be further examined as a putative therapeutic tool in neurorestorative strategies.

Key Words: BAG1; ROCK2; Raf-1 kinase; retinal ganglion cell; regeneration; apoptosis

Abbreviations: AAV, adeno-associated virus; BAG1, Bcl-2-associated athanogene-1; d.p.a., days post-axotomy; EGFP, enhanced green fluorescent protein; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; pRGC, primary retinal ganglion cell

Received December 10, 2007. Revised July 29, 2008. Accepted July 30, 2008.


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