PKD1 as a possible therapeutic target in neurodegenerative diseases

Resumen del póster presentado al 3rd Symposium on Biomedical Research: "Advances and Perspectives in Neuroscience", celebrado en la Universidad Autónoma de Madrid el 22 de abril de 2016.-- et al.Recent studies implicate excitotoxicity in a variety of neuropathological conditions, suggesting that neurodegenerative diseases with distinct genetic etiologies may share excitotoxicity as a common pathogenic pathway. Excessive activation of glutamate receptors, both NMDA and AMPA/KA subtypes leads to a number of deleterious consequences, including impairment of calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition and resulting in neuronal apoptosis and necrosis. PKD1 is a serine-threonine protein kinase that is involved in multiple biological processes. Because PKD1 has been implicated in ROS-detoxification and survival in cancer cells we hypothesized that this isoform could confer neuroprotection under excitotoxic conditions. We first investigated the possible regulation of PKD in response to overstimulation of NMDA and AMPA/KA receptors. We found a fast PKC- and Srcdependent activation of the kinase followed by a PP1-dependent inactivation during excitotoxicity. We also found that pharmacological inhibition or silencing of PKD1 decreased neuronal survival, supporting the fact that PKD inactivation is linked to neuronal death. To analyse the possible neuroprotective effects of PKD1 we generated a constitutively active mutant and cloned it in a lentiviral vector under the control of the synapsin promoter for its neurospecific expression. Transduction with this virus strongly protected neurons from excitotoxic insults by molecular mechanisms that involve potentiation of IKK/NFkB-pathway that in turn increased MnSOD levels and decreased ROS production. Together, our results demonstrate that PKD1 signaling plays a survival and detoxifications role in cortical neurons and therefore, selective and neurospecific PKD1 activators could constitute potent tools to induce neuroprotection in neurodegenerative diseases.Peer Reviewe