Klotho Protects Dopaminergic Neuron Oxidant-Induced Degeneration by Modulating ASK1 and p38 MAPK Signaling Pathways

• Published in: PloS one Vol. 10; no. 10; p. e0139914
• Main Authors: Brobey, Reynolds K, German, Dwight, Sonsalla, Patricia K, Gurnani, Prem, Pastor, Johanne, Hsieh, C-C, Papaconstantinou, John, Foster, Philip P, Kuro-o, Makoto, Rosenblatt, Kevin P
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.10.2015; Public Library of Science (PLoS)
• Subjects: Activation; Animals; Apoptosis; Biochemistry; Brain; Brain - metabolism; Brain - pathology; Cancer; Cardiovascular disease; Degeneration; Deoxyguanosine; Dopamine; Dopamine receptors; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Enzyme Activation; Fibroblasts; Genetic aspects; Glucuronidase - genetics; Glucuronidase - metabolism; Growth factors; Internal medicine; Kinases; Klotho protein; Klotho Proteins; Life assessment; MAP kinase; MAP Kinase Kinase Kinase 5 - genetics; MAP Kinase Kinase Kinase 5 - metabolism; MAP Kinase Signaling System; Medical schools; Medicine; Metabolism; Mice; Mice, Knockout; Mitochondrial DNA; Molecular biology; MPTP; Neurodegeneration; Neurons; Oxidation resistance; Oxidation-Reduction; Oxidative Stress; Oxygen; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Physiological aspects; Protein kinases; Proteomics; Reactive oxygen species; Rodents; Substantia nigra; Thioredoxin; Transgenic animals; Transgenic mice; Japan; United States > US; Texas
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0139914

Klotho transgenic mice exhibit resistance to oxidative stress as measured by their urinal levels of 8-hydroxy-2-deoxyguanosine, albeit this anti-oxidant defense mechanism has not been locally investigated in the brain. Here, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive apoptosis signal-regulating kinase 1 (ASK1)/p38 MAPK pathway regulates stress levels in the brain of these mice and showed that: 1) the ratio of free ASK1 to thioredoxin (Trx)-bound ASK1 is relatively lower in the transgenic brain whereas the reverse is true for the Klotho knockout mice; 2) the reduced p38 activation level in the transgene corresponds to higher level of ASK1-bound Trx, while the KO mice showed elevated p38 activation and lower level of-bound Trx; and 3) that 14-3-3ζ is hyper phosphorylated (Ser-58) in the transgene which correlated with increased monomer forms. In addition, we evaluated the in vivo robustness of the protection by challenging the brains of Klotho transgenic mice with a neurotoxin, MPTP and analyzed for residual neuron numbers and integrity in the substantia nigra pars compacta. Our results show that Klotho overexpression significantly protects dopaminergic neurons against oxidative damage, partly by modulating p38 MAPK activation level. Our data highlight the importance of ASK1/p38 MAPK pathway in the brain and identify Klotho as a possible anti-oxidant effector.