Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3beta phosphorylation.

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 3beta (GSK3beta) 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 GSK3beta 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.

• Authors: Zhongshu Tang, Pachiappan Arjunan, Chunsik Lee, Yang Li, Anil Kumar, Xu Hou, Bin Wang, Piotr Wardega, Fan Zhang, Lijin Dong, Yongqing Zhang, Shi-Zhuang Zhang, Hao Ding, Robert N Fariss, Kevin G Becker, Johan Lennartsson, Nobuo Nagai, Yihai Cao, Xuri Li
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 207 Issue 4 Pg. 867-80 (Apr 12 2010) ISSN: 1540-9538 [Electronic] United States
• PMID: 20231377 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Antibodies
• Apoptosis Regulatory Proteins
• Lymphokines
• Nerve Growth Factors
• Platelet-Derived Growth Factor
• platelet-derived growth factor C
• N-Methylaspartate
• Hydrogen Peroxide
• Tyrosine 3-Monooxygenase
• Receptor, Platelet-Derived Growth Factor alpha
• Receptor, Platelet-Derived Growth Factor beta
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Gsk3b protein, rat
• Glycogen Synthase Kinase 3

Topics

• Animals
• Antibodies (immunology, pharmacology)
• Apoptosis (drug effects, physiology)
• Apoptosis Regulatory Proteins (genetics)
• Brain (blood supply, cytology, drug effects, metabolism)
• Brain Ischemia (pathology, physiopathology, prevention & control)
• Capillary Permeability (drug effects)
• Cell Survival (drug effects, physiology)
• Cerebral Cortex (blood supply, drug effects, pathology)
• Female
• Gene Expression (drug effects, genetics)
• Gene Expression Profiling
• Glycogen Synthase Kinase 3 (genetics, metabolism)
• Glycogen Synthase Kinase 3 beta
• Hydrogen Peroxide (pharmacology)
• Lymphokines (antagonists & inhibitors, pharmacology, physiology, therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• N-Methylaspartate (pharmacology)
• Neovascularization, Pathologic (chemically induced)
• Nerve Growth Factors (genetics)
• Neurons (cytology, drug effects, metabolism)
• Optic Nerve Injuries (drug therapy, pathology)
• Parkinson Disease, Secondary (chemically induced, drug therapy, metabolism, pathology)
• Phosphorylation (drug effects, physiology)
• Platelet-Derived Growth Factor (antagonists & inhibitors, pharmacology, physiology, therapeutic use)
• Rats
• Receptor, Platelet-Derived Growth Factor alpha (genetics, immunology, metabolism)
• Receptor, Platelet-Derived Growth Factor beta (genetics, immunology, metabolism)
• Retina (cytology, drug effects, metabolism)
• Retinal Ganglion Cells (cytology, drug effects, metabolism)
• Retinal Vessels (anatomy & histology, drug effects)
• Stroke Volume (physiology)
• Substantia Nigra (drug effects, metabolism, pathology)
• Tyrosine 3-Monooxygenase (genetics, metabolism)