ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 NTR non-cell-autonomous signaling pathway

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-02, Vol.107 (8), p.3817-3822
• Main Authors: Lebrun-Julien, Frédéric, Bertrand, Mathieu J., De Backer, Olivier, Stellwagen, David, Morales, Carlos R., Di Polo, Adriana, Barker, Philip A.
• Format: Article
• Language: English
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0909276107

Neurotrophin binding to the p75 neurotrophin receptor (p75 NTR ) activates neuronal apoptosis following adult central nervous system injury, but the underlying cellular mechanisms remain poorly defined. In this study, we show that the proform of nerve growth factor (proNGF) induces death of retinal ganglion cells in adult rodents via a p75 NTR -dependent signaling mechanism. Expression of p75 NTR in the adult retina is confined to Müller glial cells; therefore we tested the hypothesis that proNGF activates a non-cell-autonomous signaling pathway to induce retinal ganglion cell (RGC) death. Consistent with this, we show that proNGF induced robust expression of tumor necrosis factor alpha (TNFα) in Müller cells and that genetic or biochemical ablation of TNFα blocked proNGF-induced death of retinal neurons. Mice rendered null for p75 NTR , its coreceptor sortilin, or the adaptor protein NRAGE were defective in proNGF-induced glial TNFα production and did not undergo proNGF-induced retinal ganglion cell death. We conclude that proNGF activates a non-cell-autonomous signaling pathway that causes TNFα-dependent death of retinal neurons in vivo.