Ina Eisenbach

GT-Posterpreis 2017 für Ina Eisenbach

Oxidative stress is regarded as a major trigger for neuronal dysfunction and death in the ageing brain and in multiple neurodegenerative disorders. How oxidative stress mediates neuronal death and whether the associated mechanisms are accessible for therapeutic intervention strategies is not clarified. Increasing evidence suggests that oxidative stress triggers mechanisms of regulated necrosis that involve the activation of receptor interacting protein 1 (RIP1) independently of death receptor activation.

Recently, we identified a pivotal role for cylindromatosis (CYLD) driving RIP1 activation and necrosome formation in oxidative death pathways in neurons. In a model of glutamate-induced oxidative death (oxytosis) in neuronal HT-22 cells we characterized protective effects of siRNA-mediated CYLD gene silencing which involved inhibition of RIP1/RIP3 complex formation. Additionally, experiments in CYLD-/- mice revealed protection against traumatic brain injury demonstrating an important function of CYLD in acute neuronal injury in vivo. Since oxytosis and ferroptosis share common features in their signaling pathways, like GSH depletion and inhibition of GPX4, increased lipid peroxidation and mitochondrial damage, it was of great interest to investigate a potential role of CYLD in mitochondrial death pathways in paradigms of erastin-induced ferroptosis.

Here, we show in neuronal HT-22 cells that erastin-mediated formation of reactive oxygen species (ROS) triggers mechanisms of regulated necrosis independent of TNFα-signaling. In this model system of ferroptosis, erastin promotes glutathione depletion and lipid peroxidation followed by activation of RIP1 and subsequent RIP1/RIP3 necrosome formation which is regarded as a hallmark of regulated necrosis. Silencing of RIP1 by siRNA or by the RIP1 inhibitor necrostatin-1 prevented erastin-induced cell death. In contrast, the ferroptosis inhibitor ferrostatin-1 failed to protect cells against TNF α-induced classical necroptosis, a form of programmed cell death that is mediated by RIP-kinases downstream of death receptor activation. In further steps, the impact of CYLD was investigated by siRNA-mediated gene silencing or gene knockout via the CRISPR/Cas-9 system, respectively. In erastin-induced ferroptosis, CYLD depletion decreased RIP1/RIP3 complex formation and promoted neuronal survival. Furthermore, we revealed the involvement of mitochondrial fission regulating dynamin-related protein 1 (DRP-1) since genetic depletion or pharmacological inhibition of DRP-1 protected HT-22 cells against erastin toxicity. CYLD knockout prevented erastin-induced DRP-1 translocation to mitochondria as well as mitochondrial ROS production and the loss of mitochondrial membrane potential, suggesting that CYLD and DRP-1 can link mechanisms of regulated necrosis to mitochondrial pathways of cell death in paradigms of oxidative stress

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