Journal Article

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

Véronique Planchamp, Christina Bermel, Lars Tönges, Thomas Ostendorf, Sebastian Kügler, John C. Reed, Pawel Kermer, Mathias Bähr and Paul Lingor

in Brain

Published on behalf of The Guarantors of Brain

Volume 131, issue 10, pages 2606-2619
Published in print October 2008 | ISSN: 0006-8950
Published online August 2008 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awn196
BAG1 promotes axonal outgrowth and regeneration in vivo via Raf-1 and reduction of ROCK activity

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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.

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

Journal Article.  8803 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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