A novel oxidative stress detoxification pathway that confers neuroprotection

Trabajo presentado en la Conference Achucarro Basque Center for Neuroscience, celebrada en Leioa (España) el 22 de noviembre de 2019.Excitotoxicity is a type of neuronal death that occurs by acute brain damage, such as stroke and traumatic brain injury, as well as in chronic neurodegenerative diseases including Alzheimer's or Parkinson's disease. Excitotoxicity arises from a massive release of the neurotransmitter glutamate and is associated with mitochondrial dysfunction and generation of high levels of reactive oxygen species (ROS) and oxidative stress damage. Protein kinase D1 (PKD1) is involved in multiple biological processes and is activated in vitro by oxidative stress in cancer cells through different pathways. One of these pathways promotes survival through the induction of an IKK/NF-κB oxidative stress detoxification pathway while the other is linked to cell death. We have studied the effect of excitotoxicity and neuronal ROS production on PKD1 activity, and how this could affect neuronal survival. Using in vitro and in vivo murine models, as well as human ischemic stroke samples, we have found that excitotoxicity provokes dephosphorylation and inactivation of neuronal PKD accompanied by a shut-off of the pro-survival oxidative stress detoxification pathway. In addition, and through the use of pharmacological inhibitors, lentiviral silencing and neuronal conditional knockout mice, we have demonstrated that the elimination of PKD1 in neurons exacerbates excitotoxic neuronal death. Consistently, dephosphorylation-resistant active PKD1 maintained active IKK/NF-κB survival cascade and decreased neuronal death in in vitro and in vivo models of excitotoxicity. In summary, our results demonstrate the importance of preserving PKD1 activity for neuronal survival and ROS-detoxification. PKD1 and phosphosphatases involved in its regulation could be promising targets for preventive or curative treatment of excitotoxic brain damage associated to acute and chronic neurodegeneration