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

Julia Pose-Utrilla, Lucía García-Guerra, Ana Puerto, Abraham Martín, Jerónimo Jurado-Arjona, Noelia S. León-Reyes, Andrea Gamir-Morralla, Álvaro Sebastián-Serrano, Mónica García-Gallo, Leonor Kremer, Jens Fielitz, Christofer Ireson, José Pérez-Álvarez Mª, Isidro Ferrer, Félix Hernández, Jesús Ávila, Marina Lasa, Miguel R. Campanero and Teresa Iglesias ()
Additional contact information
Julia Pose-Utrilla: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM)
Lucía García-Guerra: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM)
Ana Puerto: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM)
Abraham Martín: CIC biomaGUNE
Jerónimo Jurado-Arjona: Instituto de Salud Carlos III
Noelia S. León-Reyes: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM)
Andrea Gamir-Morralla: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM)
Álvaro Sebastián-Serrano: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM)
Mónica García-Gallo: Consejo Superior de Investigaciones Científicas (CSIC)
Leonor Kremer: Consejo Superior de Investigaciones Científicas (CSIC)
Jens Fielitz: Max-Delbrück-Center (MDC) for Molecular Medicine in the Helmholtz Association
Christofer Ireson: Cancer Research Technology
José Pérez-Álvarez Mª: Instituto de Salud Carlos III
Isidro Ferrer: Instituto de Salud Carlos III
Félix Hernández: Instituto de Salud Carlos III
Jesús Ávila: Instituto de Salud Carlos III
Marina Lasa: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM)
Miguel R. Campanero: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM)
Teresa Iglesias: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM)

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02322-5

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