Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3beta phosphorylation.
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.
National Eye Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Zhongshu
Z
Tang
Pachiappan
P
Arjunan
Chunsik
C
Lee
Yang
Y
Li
Anil
A
Kumar
Xu
X
Hou
Bin
B
Wang
Piotr
P
Wardega
Fan
F
Zhang
Lijin
L
Dong
Yongqing
Y
Zhang
Shi-Zhuang
SZ
Zhang
Hao
H
Ding
Robert N
RN
Fariss
Kevin G
KG
Becker
Johan
J
Lennartsson
Nobuo
N
Nagai
Yihai
Y
Cao
Xuri
X
Li
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001921:Brain / Q000098:blood supply / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D002199:Capillary Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000139:chemically induced; D009414:Nerve Growth Factors / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012171:Retinal Vessels / Q000033:anatomy & histology / Q000187:drug effects; D013318:Stroke Volume / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D008222:Lymphokines; D009414:Nerve Growth Factors; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C; D016202:N-Methylaspartate; D006861:Hydrogen Peroxide; D014446:Tyrosine 3-Monooxygenase; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3