MPTP activates ASK1-p38 MAPK signaling pathway through TNF-dependent Trx1 oxidation in parkinsonism mouse model

Ray, Ajit and Sehgal, Neha and Karunakaran, Smitha and Rangarajan, Govindan and Ravindranath, Vijayalakshmi (2015) MPTP activates ASK1-p38 MAPK signaling pathway through TNF-dependent Trx1 oxidation in parkinsonism mouse model. In: FREE RADICAL BIOLOGY AND MEDICINE, 87 . pp. 312-325.

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Abstract

Activation of apoptosis signal regulating kinase 1 (ASK1)-p38 MAPK death signaling cascade is irn plicated 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 1)38 MAPK in a time dependent manner in VMB alone. This occurred through selective protein thiol oxidation of the redox-sensitive thiol disulfide oxidoreductase, thiorcdoxin (Trxl), resulting in release of its inhibitory association with ASK1, while glutathione-S-transferase ji 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 ovariation netvvork analysis (PCNA) using protein states as nodes revealed TNF to be an important node regulating the ASK1 signaling cascade. In confirmation, blocking MPTP-mecliated TNF signaling through intrathecal administration of TNFneutralizing antibody prevented Trxl 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. (C) 2015 Published by Elsevier Inc.

Item Type:	Journal Article
Publication:	FREE RADICAL BIOLOGY AND MEDICINE
Publisher:	ELSEVIER SCIENCE INC
Additional Information:	Copy right for this article belongs to the ELSEVIER SCIENCE INC, 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
Keywords:	Thiols; Oxidative stress; Cell death; Graph theory; Neurodegeneration
Department/Centre:	Division of Interdisciplinary Sciences > Centre for Nano Science and Engineering Division of Physical & Mathematical Sciences > Mathematics
Date Deposited:	18 Nov 2015 10:21
Last Modified:	18 Nov 2015 10:21
URI:	http://eprints.iisc.ac.in/id/eprint/52768

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