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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Antibodies / immunology
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Antibodies / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins / genetics
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Brain / blood supply
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Brain / cytology*
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Brain / drug effects
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Brain / metabolism
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Brain Ischemia / pathology
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Brain Ischemia / physiopathology
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Brain Ischemia / prevention & control
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Capillary Permeability / drug effects
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Cell Survival / drug effects
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Cell Survival / physiology*
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Cerebral Cortex / blood supply
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Cerebral Cortex / drug effects
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Cerebral Cortex / pathology
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Female
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Gene Expression / drug effects
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Gene Expression / genetics
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Gene Expression Profiling
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism*
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Glycogen Synthase Kinase 3 beta
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Hydrogen Peroxide / pharmacology
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Lymphokines / antagonists & inhibitors
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Lymphokines / pharmacology
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Lymphokines / physiology*
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Lymphokines / therapeutic use
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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N-Methylaspartate / pharmacology
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Neovascularization, Pathologic / chemically induced
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Nerve Growth Factors / genetics
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Neurons / cytology*
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Neurons / drug effects
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Neurons / metabolism
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Optic Nerve Injuries / drug therapy
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Optic Nerve Injuries / pathology
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Parkinson Disease, Secondary / chemically induced
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Parkinson Disease, Secondary / drug therapy
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Parkinson Disease, Secondary / metabolism
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Parkinson Disease, Secondary / pathology
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Phosphorylation / drug effects
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Phosphorylation / physiology
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Platelet-Derived Growth Factor / antagonists & inhibitors
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Platelet-Derived Growth Factor / pharmacology
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Platelet-Derived Growth Factor / physiology*
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Platelet-Derived Growth Factor / therapeutic use
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Rats
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Receptor, Platelet-Derived Growth Factor alpha / genetics
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Receptor, Platelet-Derived Growth Factor alpha / immunology
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Receptor, Platelet-Derived Growth Factor alpha / metabolism
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Receptor, Platelet-Derived Growth Factor beta / genetics
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Receptor, Platelet-Derived Growth Factor beta / immunology
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Receptor, Platelet-Derived Growth Factor beta / metabolism
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Retina / cytology*
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Retina / drug effects
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Retina / metabolism
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Retinal Ganglion Cells / cytology
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Retinal Ganglion Cells / drug effects
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Retinal Ganglion Cells / metabolism
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Retinal Vessels / anatomy & histology
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Retinal Vessels / drug effects
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Stroke Volume / physiology
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Substantia Nigra / drug effects
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Substantia Nigra / metabolism
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Substantia Nigra / pathology
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Tyrosine 3-Monooxygenase / genetics
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Tyrosine 3-Monooxygenase / metabolism
Substances
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Antibodies
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Apoptosis Regulatory Proteins
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Lymphokines
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Nerve Growth Factors
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Platelet-Derived Growth Factor
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platelet-derived growth factor C
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N-Methylaspartate
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Hydrogen Peroxide
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Tyrosine 3-Monooxygenase
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Receptor, Platelet-Derived Growth Factor alpha
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Receptor, Platelet-Derived Growth Factor beta
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Gsk3b protein, rat
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Glycogen Synthase Kinase 3