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Abstract #25637 Published in IGR 12-1
ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway
Lebrun-Julien F; Bertrand MJ; De Backer O; Stellwagen D; Morales CR; Di Polo A; Barker PAProceedings of the National Academy of Sciences of the United States of America 2010; 107: 3817-3822
ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway Neurotrophin binding to the p75 neurotrophin receptor (p75NTR) 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 p75NTR-dependent signaling mechanism. Expression of p75NTR 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 (TNFalpha) in Müller cells and that genetic or biochemical ablation of TNFalpha blocked proNGF-induced death of retinal neurons. Mice rendered null for p75NTR, its coreceptor sortilin, or the adaptor protein NRAGE were defective in proNGF-induced glial TNFalpha production and did not undergo proNGF-induced retinal ganglion cell death. We conclude that proNGF activates a non-cell-autonomous signaling pathway that causes TNFalpha-dependent death of retinal neurons in vivo.
Classification:
3.6 Cellular biology (Part of: 3 Laboratory methods)
1.3 Pathogenesis (Part of: 1 General aspects)
11.8 Neuroprotection (Part of: 11 Medical treatment)
