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

• Published in: Neurobiology of disease 2005-10, Vol.20 (1), p.141-154
• Main Authors: Onyango, Isaac G, Tuttle, Jeremy B, Bennett, Jr, James P
• Format: Article
• Language: English
• Subjects: Aged; Apoptosis; Brain-Derived Neurotrophic Factor - metabolism; Brain-Derived Neurotrophic Factor - pharmacology; Cell Death - drug effects; Cell Death - physiology; Cell Survival - drug effects; Cell Survival - physiology; Cybrids; Cytoprotection - drug effects; Cytoprotection - physiology; Female; Glial Cell Line-Derived Neurotrophic Factor - metabolism; Glial Cell Line-Derived Neurotrophic Factor - pharmacology; Humans; Hybrid Cells; Hydrogen Peroxide - antagonists & inhibitors; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Middle Aged; Mitochondria; Nerve Degeneration - chemically induced; Nerve Degeneration - drug therapy; Nerve Degeneration - metabolism; Neuroprotective Agents - metabolism; Neuroprotective Agents - pharmacology; Neurotrophins; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; Parkinson's disease; Phosphatidylinositol 3-Kinases - drug effects; Phosphatidylinositol 3-Kinases - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; src-Family Kinases - drug effects; src-Family Kinases - metabolism
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2005.02.009

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.