Abstract
Glial cell-line-derived neurotrophic factor (GDNF) and neurturin (NTN) protect retinal ganglion cells (RGCs) from axotomy-induced apoptosis. It is likely that neuroprotection by GDNF or NTN in the adult central nervous system (CNS) involves indirect mechanisms and independent signal transduction events. Extracellular glutamate is a trigger of apoptosis in injured RGCs, and glutamate transporter levels can be upregulated by GDNF. Therefore, GDNF may indirectly protect RGCs by enhancing glutamate uptake in the retina. We studied the upregulation of the glutamate transporters GLAST-1 and GLT-1 by GDNF and NTN, and the intracellular pathways required for GDNF/NTN neuroprotection. GDNF required phosphoinositide-3 kinase (PI3K) and Src activity to upregulate GLAST-1 and GLT-1. NTN required PI3K activity to upregulate GLAST-1 and did not affect GLT-1 levels. PI3K activity was also important for GDNF and NTN neuroprotection following optic nerve transection. However, GDNF also required Src and mitogen-activated protein kinase activity to prevent RGC apoptosis. RNA interference demonstrated that the upregulation of GLAST-1 by GDNF and NTN is required to rescue RGCs. Thus, additional independent signal transduction events, together with the upregulation of GLT-1 by GDNF, differentiate the biological activity of GDNF from NTN. Furthermore, the upregulation of the glial glutamate transporter GLAST-1 by both factors is an indirect neuroprotective mechanism in the CNS.
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Abbreviations
- GDNF:
-
glial cell-line-derived neurotrophic factor
- NTN:
-
neurturin
- BDNF:
-
brain-derived neurotrophic factor
- GLAST-1:
-
L-glutamate/L-aspartate transporter
- GLT-1:
-
L-glutamate transporter
- GS:
-
glutamine synthetase
- PI3K:
-
phosphoinositide-3 kinase
- MAPK:
-
mitogen-activated protein kinase
- Src:
-
sarcoma
- RGC:
-
retinal ganglion cell
References
Koeberle PD, Bahr M . Growth and guidance cues for regenerating axons: where have they gone? J Neurobiol 2004; 59: 162–180.
Klocker N, Braunling F, Isenmann S, Bahr M . In vivo neurotrophic effects of GDNF on axotomized retinal ganglion cells. Neuroreport 1997; 8: 3439–3442.
Koeberle PD, Ball AK . Effects of GDNF on retinal ganglion cell survival following axotomy. Vision Res 1998; 38: 1505–1515.
Koeberle PD, Ball AK . Neurturin enhances the survival of axotomized retinal ganglion cells in vivo: combined effects with glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor. Neuroscience 2002; 110: 555–567.
Jomary C, Thomas M, Grist J, Milbrandt J, Neal MJ, Jones SE . Expression patterns of neurturin and its receptor components in developing and degenerative mouse retina. Invest Ophthalmol Vis Sci 1999; 40: 568–574.
Airaksinen MS, Saarma M . The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 2002; 3: 383–394.
Dreyer EB, Pan ZH, Storm S, Lipton SA . Greater sensitivity of larger retinal ganglion cells to NMDA-mediated cell death. Neuroreport 1994; 5: 629–631.
Vorwerk CK, Kreutz MR, Bockers TM, Brosz M, Dreyer EB, Sabel BA . Susceptibility of retinal ganglion cells to excitotoxicity depends on soma size and retinal eccentricity. Curr Eye Res 1999; 19: 59–65.
Levy DI, Lipton SA . Comparison of delayed administration of competitive and uncompetitive antagonists in preventing NMDA receptor-mediated neuronal death. Neurology 1990; 40: 852–855.
Schuettauf F, Naskar R, Vorwerk CK, Zurakowski D, Dreyer EB . Ganglion cell loss after optic nerve crush mediated through AMPA-kainate and NMDA receptors. Invest Ophthalmol Vis Sci 2000; 41: 4313–4316.
Russelakis-Carneiro M, Silveira LC, Perry VH . Factors affecting the survival of cat retinal ganglion cells after optic nerve injury. J Neurocytol 1996; 25: 393–402.
Yoles E, Muller S, Schwartz M . NMDA-receptor antagonist protects neurons from secondary degeneration after partial optic nerve crush. J Neurotrauma 1997; 14: 665–675.
Kikuchi M, Tenneti L, Lipton SA . Role of p38 mitogen-activated protein kinase in axotomy-induced apoptosis of rat retinal ganglion cells. J Neurosci 2000; 20: 5037–5044.
Derouiche A, Rauen T . Coincidence of L-glutamate/L-aspartate transporter (GLAST) and glutamine synthetase (GS) immunoreactions in retinal glia: evidence for coupling of GLAST and GS in transmitter clearance. J Neurosci Res 1995; 42: 131–143.
Lehre KP, Davanger S, Danbolt NC . Localization of the glutamate transporter protein GLAST in rat retina. Brain Res 1997; 744: 129–137.
Rauen T, Rothstein JD, Wassle H . Differential expression of three glutamate transporter subtypes in the rat retina. Cell Tissue Res 1996; 286: 325–336.
Vorwerk CK, Naskar R, Schuettauf F, Quinto K, Zurakowski D, Gochenauer G et al. Depression of retinal glutamate transporter function leads to elevated intravitreal glutamate levels and ganglion cell death. Invest Ophthalmol Vis Sci 2000; 41: 3615–3621.
Rauen T, Kanner BI . Localization of the glutamate transporter GLT-1 in rat and macaque monkey retinae. Neurosci Lett 1994; 169: 137–140.
Harada T, Harada C, Watanabe M, Inoue Y, Sakagawa T, Nakayama N et al. Functions of the two glutamate transporters GLAST and GLT-1 in the retina. Proc Natl Acad Sci USA 1998; 95: 4663–4666.
Lindqvist N, Peinado-Ramonn P, Vidal-Sanz M, Hallbook F . GDNF, Ret, GFRalpha1 and 2 in the adult rat retino-tectal system after optic nerve transection. Exp Neurol 2004; 187: 487–499.
Jelsma TN, Friedman HH, Berkelaar M, Bray GM, Aguayo AJ . Different forms of the neurotrophin receptor trkB mRNA predominate in rat retina and optic nerve. J Neurobiol 1993; 24: 1207–1214.
Johnson JE, Barde YA, Schwab M, Thoenen H . Brain-derived neurotrophic factor supports the survival of cultured rat retinal ganglion cells. J Neurosci 1986; 6: 3031–3038.
Guidry C . Isolation and characterization of porcine Muller cells. Myofibroblastic dedifferentiation in culture. Invest Ophthalmol Vis Sci 1996; 37: 740–752.
McGillem GS, Guidry C, Dacheux RF . Antigenic changes of rabbit retinal Muller cells in culture. Invest Ophthalmol Vis Sci 1998; 39: 1453–1461.
Vlahos CJ, Matter WF, Hui KY, Brown RF . A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 1994; 269: 5241–5248.
Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR . PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 1995; 270: 27489–27494.
Hanke JH, Gardner JP, Dow RL, Changelian PS, Brissette WH, Weringer EJ et al. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J Biol Chem 1996; 271: 695–701.
Furuta A, Rothstein JD, Martin LJ . Glutamate transporter protein subtypes are expressed differentially during rat CNS development. J Neurosci 1997; 17: 8363–8375.
Conradt M, Storck T, Stoffel W . Localization of N-glycosylation sites and functional role of the carbohydrate units of GLAST-1, a cloned rat brain L-glutamate/L-aspartate transporter. Eur J Biochem 1995; 229: 682–687.
Schlag BD, Vondrasek JR, Munir M, Kalandadze A, Zelenaia OA, Rothstein JD et al. Regulation of the glial Na+-dependent glutamate transporters by cyclic AMP analogs and neurons. Mol Pharmacol 1998; 53: 355–369.
Raunser S, Haase W, Bostina M, Parcej DN, Kuhlbrandt W . High-yield expression, reconstitution and structure of the recombinant, fully functional glutamate transporter GLT-1 from Rattus norvegicus. J Mol Biol 2005; 351: 598–613.
Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D et al. Localization of neuronal and glial glutamate transporters. Neuron 1994; 13: 713–725.
Rauen T, Wiessner M . Fine tuning of glutamate uptake and degradation in glial cells: common transcriptional regulation of GLAST1 and GS. Neurochem Int 2000; 37: 179–189.
Chaturvedi LS, Marsh HM, Basson MD . Src and focal adhesion kinase mediate mechanical strain-induced proliferation and ERK1/2 phosphorylation in human H441 pulmonary epithelial cells. Am J Physiol Cell Physiol 2007; 292: C1701–C1713.
Guo J, Wu HW, Hu G, Han X, De W, Sun YJ . Sustained activation of Src-family tyrosine kinases by ischemia: a potential mechanism mediating extracellular signal-regulated kinase cascades in hippocampal dentate gyrus. Neuroscience 2006; 143: 827–836.
Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 2005; 433: 73–77.
Nicole O, Ali C, Docagne F, Plawinski L, MacKenzie ET, Vivien D et al. Neuroprotection mediated by glial cell line-derived neurotrophic factor: involvement of a reduction of NMDA-induced calcium influx by the mitogen-activated protein kinase pathway. J Neurosci 2001; 21: 3024–3033.
Vorwerk CK, Naskar R, Schuettauf F, Quinto K, Zurakowski D, Gochenauer G et al. Depression of retinal glutamate transporter function leads to elevated intravitreal glutamate levels and ganglion cell death. Invest Ophthalmol Vis Sci 2000; 41: 3615–3621.
Brooks DE, Komaromy AM, Kallberg ME . Comparative retinal ganglion cell and optic nerve morphology. Vet Ophthalmol 1999; 2: 3–11.
Hanke JH, Gardner JP, Dow RL, Changelian PS, Brissette WH, Weringer EJ et al. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J Biol Chem 1996; 271: 695–701.
Acknowledgements
This work was supported by fellowships to PDK from the Alexander von Humboldt Foundation and the Natural Sciences and Engineering Research Council of Canada. We thank VP Sarthy for the rMC-1 cells.
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Koeberle, P., Bähr, M. The upregulation of GLAST-1 is an indirect antiapoptotic mechanism of GDNF and neurturin in the adult CNS. Cell Death Differ 15, 471–483 (2008). https://doi.org/10.1038/sj.cdd.4402281
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DOI: https://doi.org/10.1038/sj.cdd.4402281
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