title: MPTP activates ASK1-p38 MAPK signaling pathway through TNF-dependent Trx1 oxidation in parkinsonism mouse model.
abstract: Activation of apoptosis signal-regulating kinase 1 (ASK1)-p38 MAPK death signaling cascade is implicated in the death of dopaminergic neurons in substantia nigra in Parkinson's disease (PD). We investigated upstream activators of ASK1 using an MPTP mouse model of parkinsonism and assessed the temporal cascade of death signaling in ventral midbrain (VMB) and striatum (ST). MPTP selectively activated ASK1 and downstream p38 MAPK in a time-dependent manner in VMB alone. This occurred through selective protein thiol oxidation of the redox-sensitive thiol disulfide oxidoreductase, thioredoxin (Trx1), resulting in release of its inhibitory association with ASK1, while glutathione-S-transferase µ 1 (GSTM1) remained in reduced form in association with ASK1. Levels of tumor necrosis factor (TNF), a known activator of ASK1, increased early after MPTP in VMB. Protein covariation network analysis (PCNA) using protein states as nodes revealed TNF to be an important node regulating the ASK1 signaling cascade. In confirmation, blocking MPTP-mediated TNF signaling through intrathecal administration of TNF-neutralizing antibody prevented Trx1 oxidation and downstream ASK1-p38 MAPK activation. Averting an early increase in TNF, which leads to protein thiol oxidation resulting in activation of ASK1-p38 signaling, may be critical for neuroprotection in PD. Importantly, network analysis can help in understanding the cause/effect relationship within protein networks in complex disease states.
authors.affiliation: National Brain Research Centre, Nainwal Mode, Manesar-122051, India; Centre for Neuroscience, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Ajit
authors.initials: A
authors.lastname: Ray
authors.affiliation: National Brain Research Centre, Nainwal Mode, Manesar-122051, India.
authors.forename: Neha
authors.initials: N
authors.lastname: Sehgal
authors.affiliation: National Brain Research Centre, Nainwal Mode, Manesar-122051, India.
authors.forename: Smitha
authors.initials: S
authors.lastname: Karunakaran
authors.affiliation: Department of Mathematics, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Govindan
authors.initials: G
authors.lastname: Rangarajan
authors.affiliation: Centre for Neuroscience, Indian Institute of Science, Bangalore 560012, India. Electronic address: viji@cns.iisc.ernet.in.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Ravindranath
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013879:Thioredoxins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D014409:Tumor Necrosis Factor-alpha; C515559:Txn1 protein, mouse; D013879:Thioredoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse
keywords: Cell death; Graph theory; Neurodegeneration; Oxidative stress; Thiols