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Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1

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Item Type:Article
Title:Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1
Creators Name:Pose-Utrilla, J. and García-Guerra, L. and Del Puerto, A. and Martin, A. and Jurado-Arjona, J. and De León-Reyes, N.S. and Gamir-Morralla, A. and Sebastián-Serrano, A. and García-Gallo, M. and Kremer, L. and Fielitz, J. and Ireson, C. and Pérez-Álvarez, M.J. and Ferrer, I. and Hernández, F. and Ávila, J. and Lasa, M. and Campanero, M.R. and Iglesias, T.
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-κB/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-κB/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.
Keywords:Cell Death, Dual Specificity Phosphatase 1, I-kappa B Kinase, In Vitro Techniques, Knockout Mice, Neurons, Neuroprotection, NF-kappa B, Oxidative Stress, Phosphorylation, Protein Kinase C, Protein Phosphatase 1, Signal Transduction, Superoxide Dismutase, Animals, Mice
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group (U.K.)
Volume:8
Number:1
Page Range:2275
Date:22 December 2017
Additional Information:Erratum in: Nat Commun 9(1): 473.
Official Publication:https://doi.org/10.1038/s41467-017-02322-5
PubMed:View item in PubMed

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