SorCS2 Controls Functional Expression of Amino Acid Transporter EAAT3 and Protects Neurons from Oxidative Stress and Epilepsy-Induced Pathology

Abstract

Summary: VPS10P domain receptors emerge as central regulators of intracellular protein sorting in neurons with relevance for various brain pathologies. Here, we identified a role for the family member SorCS2 in protection of neurons from oxidative stress and epilepsy-induced cell death. We show that SorCS2 acts as sorting receptor that sustains cell surface expression of the neuronal amino acid transporter EAAT3 to facilitate import of cysteine, required for synthesis of the reactive oxygen species scavenger glutathione. Lack of SorCS2 causes depletion of EAAT3 from the plasma membrane and impairs neuronal cysteine uptake. As a consequence, SorCS2-deficient mice exhibit oxidative brain damage that coincides with enhanced neuronal cell death and increased mortality during epilepsy. Our findings highlight a protective role for SorCS2 in neuronal stress response and provide a possible explanation for upregulation of this receptor seen in surviving neurons of the human epileptic brain. : Malik et al. uncover a mechanism crucial for neuronal oxidative stress defense. They show that sorting receptor SorCS2 facilitates cell surface expression of cysteine transporter EAAT3. Loss of Sorcs2 impairs neuronal cysteine import and glutathione production, increases vulnerability to oxidative damage, and aggravates epilepsy-induced brain pathology and death in mice. Keywords: VPS10P domain receptors, intracellular protein sorting, oxidative stress, EAAT3, EAAC1, epilepsy, glutathione