Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylcysteine / pharmacology
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Aged
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Antioxidants / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology*
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Collagen Type XI / metabolism
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DNA, Mitochondrial / physiology
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Enzyme Inhibitors / pharmacology
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Female
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Gene Amplification / physiology
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Humans
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Hybrid Cells / drug effects
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Hybrid Cells / metabolism*
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JNK Mitogen-Activated Protein Kinases / drug effects
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Male
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Middle Aged
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NF-kappa B / metabolism
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Oxidative Stress / drug effects
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Oxidative Stress / physiology
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Parkinson Disease / metabolism*
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Parkinson Disease / physiopathology
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Up-Regulation / physiology
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p38 Mitogen-Activated Protein Kinases / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Antioxidants
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COL11A2 protein, human
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Collagen Type XI
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DNA, Mitochondrial
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Enzyme Inhibitors
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NF-kappa B
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PARP1 protein, human
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Acetylcysteine