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ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway.

ABSTRACT: 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 (TNFalpha) in Müller cells and that genetic or biochemical ablation of TNFalpha 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 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.

SUBMITTER: Lebrun-Julien F

PROVIDER: S-EPMC2840442 | biostudies-other | 2010 Feb

REPOSITORIES: biostudies-other

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ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway.

Lebrun-Julien Frédéric F Bertrand Mathieu J MJ De Backer Olivier O Stellwagen David D Morales Carlos R CR Di Polo Adriana A Barker Philip A PA

Proceedings of the National Academy of Sciences of the United States of America 20100203 8

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 proN ...[more]

PMID: 20133718

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Project description:High pressure is the most important factor inducing retinal ganglion cell (RGC) apoptosis. However, the underlying mechanisms remain obscure. The present study investigated the effects of different levels of hydrostatic pressure (HP) on RGCs and the potential mechanisms involved. Primary cultured rat RGCs were exposed to five levels of HP (0, 20, 40, 60 and 80 mmHg) for 24 h. Morphological changes in RGCs were observed. The viability and apoptosis rate of RGCs were detected using a Cell Counting Kit‑8 assay and Annexin V‑fluorescein isothiocyanate/propidium iodide flow cytometry, respectively. Western blotting, reverse transcription‑quantitative polymerase chain reaction and immunofluorescence were used to detect the expression and mRNA levels of nerve growth factor (NGF), protein kinase B (AKT), apoptosis signal‑regulating kinase 1 (ASK1), forkhead box O1 (FoxO1) and cAMP response element binding protein (CREB). In the 0‑ and 20‑mmHg groups, there were no apoptotic morphological changes. In the 40 mmHg group, parts of the cell were shrunken or disrupted. In the 60 mmHg group, neurite extension was weakened and parts of the cells were disintegrating or dying. In the 80 mmHg group, the internal structures of the cells were not visible at all. The apoptosis rates of RGCs were significantly higher and the viability rates significantly lower under 40, 60 and 80 mmHg compared with under 0 or 20 mmHg (all P<0.01). The expression and mRNA levels of NGF, AKT and CREB decreased in a dose‑dependent manner in the 40‑, 60‑ and 80‑mmHg groups (all P<0.05), but those of ASK1 and FoxO1 increased in a dose‑dependent manner (all P<0.05). Interestingly, the alterations to the expression and mRNA levels of CREB were significantly larger compared with the changes in ASK1 or FoxO1 in the 40‑, 60‑ and 80‑mmHg groups (all P<0.01). The results of the present study demonstrate that elevated HP of 40, 60 or 80 mmHg reduces viability and induces apoptosis in RGCs, which may occur through effects on the NGF/ASK1/FoxO1 and NGF/AKT/CREB pathways, of which the latter is more strongly affected.

Dataset Information

ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway.

Publications

ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway.

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