Brain-derived growth factor and glial cell line-derived growth factor use distinct intracellular signaling pathways to protect PD cybrids from H2O2-induced neuronal death.
The cause of idiopathic PD is obscure, and most cases are sporadic. Oxidative stress and deficiency of various neurotrophic factors (NTFs) could be factors triggering neurodegeneration in the substantia nigra (SN). Cytoplasmic hybrid cells (cybrids) made from mitochondrial DNA of idiopathic PD subjects have reduced glutathione (GSH) levels and increased vulnerability to H2O2. Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) rescue PD cybrids from H2O2-induced cell death. GDNF mediated effects require Src kinase and phosphatidylinositol 3-kinase (PI3K)/Akt activation. Inhibiting either PI3K/Akt or ERK pathways blocks the effects of BDNF. Inhibiting p38MAPK and c-Jun N-terminal kinase (JNK) pathways enhances the neuroprotective effects of both NTFs. These results demonstrate that expression of PD mitochondrial genes in cybrids increases vulnerability to oxidative stress that is ameliorated by both BDNF and GDNF, which utilize distinct signaling cascades to increase intracellular GSH and enhance survival-promoting cell signaling.
Onyango
Isaac G
IG
Department of Neuroscience, University of Virginia School of Medicine, PO Box 801392, Charlottesville, VA 22908, USA. Onyango@virginia.edu
Tuttle
Jeremy B
JB
Bennett
James P
JP
D000368:Aged; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006822:Hybrid Cells; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases