title: Klotho Protects Dopaminergic Neuron Oxidant-Induced Degeneration by Modulating ASK1 and p38 MAPK Signaling Pathways.
abstract: 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.
authors.affiliation: Centers for Proteomics and Systems Biology, the Brown Foundation Institute of Molecular Medicine, UTHealth Medical School, 1825 Pressler Street, Houston, Texas, United States of America; Division of Oncology, Department of Internal Medicine, UTHealth Medical School, 6410 Fannin, UTPB Suite 722, Houston, Texas, United States of America.
authors.forename: Reynolds K
authors.initials: RK
authors.lastname: Brobey
authors.affiliation: Department of Psychiatry, the University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas, United States of America.
authors.forename: Dwight
authors.initials: D
authors.lastname: German
authors.affiliation: Department of Neurology, UMDNJ Robert Wood Johnson Medical Center, Piscataway, New Jersey, United States of America.
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Sonsalla
authors.affiliation: Companion Dx Reference Lab, LLC, 10301 Stella Link Rd., Suite C, Houston, Texas, United States of America.
authors.forename: Prem
authors.initials: P
authors.lastname: Gurnani
authors.affiliation: Department of Psychiatry, the University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas, United States of America.
authors.forename: Johanne
authors.initials: J
authors.lastname: Pastor
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: C-C
authors.initials: CC
authors.lastname: Hsieh
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Papaconstantinou
authors.affiliation: Centers for Proteomics and Systems Biology, the Brown Foundation Institute of Molecular Medicine, UTHealth Medical School, 1825 Pressler Street, Houston, Texas, United States of America; Department of NanoMedicine and Biomedical Engineering, MD Anderson Cancer Center Bldg-3SCRB, 1881 East Road, Houston, Texas, United States of America; Division of Pulmonary Medicine, Department of Internal Medicine, 6431 Fannin, MSB 1.274, Houston, Texas, United States of America.
authors.forename: Philip P
authors.initials: PP
authors.lastname: Foster
authors.affiliation: Department of Pathology, Center for Mineral Metabolism, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas, United States of America; Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-o
authors.affiliation: Centers for Proteomics and Systems Biology, the Brown Foundation Institute of Molecular Medicine, UTHealth Medical School, 1825 Pressler Street, Houston, Texas, United States of America; Companion Dx Reference Lab, LLC, 10301 Stella Link Rd., Suite C, Houston, Texas, United States of America.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Rosenblatt
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D000090265:Klotho Proteins; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D005966:Glucuronidase; D000090265:Klotho Proteins