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ADP-ribose triggers neuronal ferroptosis by rewiring purine and pyrimidine metabolism

Publicada
Servidor
bioRxiv
DOI
10.1101/2021.05.12.443941

Hyperactivation of NAD+-consuming pathways frequently occurs in neurological diseases, however therapies replenishing NAD+levels show limited therapeutic efficacy, indicating more complex underlying pathophysiology. Here, we delineate a pathogenic link between ADP-ribose —a product of NAD+consumption—and a metabolic rewiring-dependent form of neuronal ferroptosis. We demonstrate that oxidative stress induces neurons to produce ADP-ribose through the PARP1-PARG axis. ADP-ribose directly binds and inhibits the equilibrative nucleoside transporter ENT2, remodelingde novopurine and pyrimidine synthesis by hyperactivating the inosine-hypoxanthine-xanthine oxidase and glutamine-dihydroorotate-dihydroorotate dehydrogenase axes. This overproduces superoxide radicals and drives lipid peroxidation and neuronal ferroptosis. Elevated ADP-ribose levels were observed in neurological disease models, and acute ADP-ribose exposure severely reduced mouse brain neuronsin vivo. Critically, interventions blocking ADP-ribose signaling alleviated cognitive decline in mouse intracerebral hemorrhage models. Our findings characterize ADP-ribose signaling as linking NAD+consumption to neuronal ferroptosis, and provide a theraputic strategy for neuropathologies involving NAD+consumption and oxidative stress.

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