15737736

pubmed:Citation

3

Cytoplasmic hybrid cells (cybrids) are created by selective amplification of mitochondrial genes against constant nuclear genetic and environmental backgrounds. Cybrids from patients with sporadic Parkinson's disease (PD) recapitulate disease features such as decreased complex I activity, increased oxidative stress, elevated activation of NF-kappaB, and production of Lewy body inclusions. We examined the activation of signaling pathways and NF-kappaB in PD cybrids after exposure to MAPK inhibitors and/or the antioxidant N-acetylcysteine (NAC). Under basal replicating conditions, PD cybrids have decreased viability that is associated with increased DNA condensation and poly-ADP ribose polymerase (PARP) cleavage as well as elevated p38 and JNK activity. Pharmacological inhibition of oxidative stress diminished the elevated p38, JNK activity and PARP cleavage, and enhanced PD cybrid viability. PD mitochondrial genes expressed in cybrids stimulate pro-apoptotic cell signaling and biochemistry through oxidative stress. These results support development of antioxidative therapeutics for PD.

eng

IM

MEDLINE

1044-7431

Print

NLM

452-61

pubmed-meshheading:15737736-Acetylcysteine, pubmed-meshheading:15737736-Aged, pubmed-meshheading:15737736-Antioxidants, pubmed-meshheading:15737736-Apoptosis, pubmed-meshheading:15737736-Cell Survival, pubmed-meshheading:15737736-Cells, Cultured, pubmed-meshheading:15737736-Collagen Type XI, pubmed-meshheading:15737736-DNA, Mitochondrial, pubmed-meshheading:15737736-Enzyme Activation, pubmed-meshheading:15737736-Enzyme Inhibitors, pubmed-meshheading:15737736-Female, pubmed-meshheading:15737736-Gene Amplification, pubmed-meshheading:15737736-Humans, pubmed-meshheading:15737736-Hybrid Cells, pubmed-meshheading:15737736-JNK Mitogen-Activated Protein Kinases, pubmed-meshheading:15737736-Male, pubmed-meshheading:15737736-Middle Aged, pubmed-meshheading:15737736-NF-kappa B, pubmed-meshheading:15737736-Oxidative Stress, pubmed-meshheading:15737736-Parkinson Disease, pubmed-meshheading:15737736-Poly(ADP-ribose) Polymerases, pubmed-meshheading:15737736-Signal Transduction, pubmed-meshheading:15737736-Up-Regulation, pubmed-meshheading:15737736-p38 Mitogen-Activated Protein Kinases

Activation of p38 and N-acetylcysteine-sensitive c-Jun NH2-terminal kinase signaling cascades is required for induction of apoptosis in Parkinson's disease cybrids.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, N.I.H., Extramural