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Title:	Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1
Author:	Pose Utrilla, Julia; García Guerra, Lucía; Puerto, Ana Del; Martín, Abraham; Jurado Arjona, Jerónimo; León Reyes, Noelia S. De; Gamir Morralla, Andrea; Sebastián Serrano, Álvaro; García Gallo, Mónica; Kremer, Leonor; Fielitz, Jens; Ireson, Christofer; Pérez Álvarez, Mª José; Ferrer, Isidro (Ferrer Abizanda); Hernández, Félix; Avila, Jesús; Lasa, Marina; Campanero, Miguel R.; Iglesias, Teresa
Abstract:	Excitotoxicity, a critical process in neurodegeneration, induces oxidative stress and neuronal death through mechanisms largely unknown. Since oxidative stress activates protein kinase D1 (PKD1) in tumor cells, we investigated the effect of excitotoxicity on neuronal PKD1 activity. Unexpectedly, we find that excitotoxicity provokes an early inactivation of PKD1 through a dephosphorylation-dependent mechanism mediated by protein phosphatase-1 (PP1) and dual specificity phosphatase-1 (DUSP1). This step turns off the IKK/NF-kappa B/SOD2 antioxidant pathway. Neuronal PKD1 inactivation by pharmacological inhibition or lentiviral silencing in vitro, or by genetic inactivation in neurons in vivo, strongly enhances excitotoxic neuronal death. In contrast, expression of an active dephosphorylation-resistant PKD1 mutant potentiates the IKK/NF-kappa B/SOD2 oxidative stress detoxification pathway and confers neuroprotection from in vitro and in vivo excitotoxicity. Our results indicate that PKD1 inactivation underlies excitotoxicity-induced neuronal death and suggest that PKD1 inactivation may be critical for the accumulation of oxidation-induced neuronal damage during aging and in neurodegenerative disorders.
Subject(s):	-Estrès oxidatiu -Malalties neurodegeneratives -Oxidative stress -Neurodegenerative diseases
Rights:	cc by (c) Pose Utrilla et al., 2018 http://creativecommons.org/licenses/by/3.0/es/
Document type:	Article Article - Published version
Published by:	Nature Publishing Group
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