NDRG2 Protects the Brain from Excitotoxicity by Facilitating Interstitial Glutamate Uptake

Glutamate is a prominent neurotransmitter responsible for excitatory synaptic transmission and is taken up by sodium-dependent excitatory amino acid transporters (EAATs) on astrocytes to maintain synaptic homeostasis. Here, we report that N-myc downstream regulated gene 2 (NDRG2), a known tumor suppressor, is required to facilitate astroglial glutamate uptake and protect the brain from glutamate excitotoxicity after ischemia. NDRG2 knockout (Ndrg2^-/-) mice exhibited an increase in cerebral interstitial glutamate and a reduction in glutamate uptake into astrocytes. The ability of NDRG2 to control EAAT-mediated glutamate uptake into astrocytes required NDRG2 to interact with and promote the function of Na⁺/K⁺-ATPase β1, which could be disrupted by a Na⁺/K⁺-ATPase β1 peptide. The deletion of NDRG2 or treatment with the Na⁺/K⁺-ATPase β1 peptide significantly increased neuronal death upon a glutamate challenge and aggravated brain damage after ischemia. Our findings demonstrate that NDRG2 plays a pivotal role in promoting astroglial glutamate uptake from the interstitial space and protecting the brain from glutamate excitotoxicity.