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The Journal of Experimental Medicine
Year: 2010  |  Volume: 207  |  Issue: 4  |  Page No.: 867 - 880

Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3{beta} phosphorylation

Z Tang, P Arjunan, C Lee, Y Li, A Kumar, X Hou, B Wang, P Wardega, F Zhang, L Dong, Y Zhang, S. Z Zhang, H Ding, R. N Fariss, K. G Becker, J Lennartsson, N Nagai, Y Cao and X. Li    

Abstract:

Platelet-derived growth factor CC (PDGF-CC) is the third member of the PDGF family discovered after more than two decades of studies on the original members of the family, PDGF-AA and PDGF-BB. The biological function of PDGF-CC remains largely to be explored. We report a novel finding that PDGF-CC is a potent neuroprotective factor that acts by modulating glycogen synthase kinase 3β (GSK3β) activity. In several different animal models of neuronal injury, such as axotomy-induced neuronal death, neurotoxin-induced neuronal injury, 6-hydroxydopamine–induced Parkinson’s dopaminergic neuronal death, and ischemia-induced stroke, PDGF-CC protein or gene delivery protected different types of neurons from apoptosis in both the retina and brain. On the other hand, loss-of-function assays using PDGF-C null mice, neutralizing antibody, or short hairpin RNA showed that PDGF-CC deficiency/inhibition exacerbated neuronal death in different neuronal tissues in vivo. Mechanistically, we revealed that the neuroprotective effect of PDGF-CC was achieved by regulating GSK3β phosphorylation and expression. Our data demonstrate that PDGF-CC is critically required for neuronal survival and may potentially be used to treat neurodegenerative diseases. Inhibition of the PDGF-CC–PDGF receptor pathway for different clinical purposes should be conducted with caution to preserve normal neuronal functions.

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