SorCS2 controls functional expression of amino acid transporter EAAT3 to protect neurons from oxidative stress and epilepsy-induced pathology

The family of VPS10P domain receptors emerges as central regulator of intracellular protein sorting in neurons with relevance for various brain pathologies. Here, we identified a unique role for the family member SorCS2 in protection of neurons from oxidative stress and from epilepsy-induced cell death. We show that SorCS2 acts as sorting receptor that targets the neuronal amino acid transporter EAAT3 to the plasma membrane to facilitate import of cysteine, required for synthesis of the reactive oxygen species scavenger glutathione. Absence of SorCS2 activity causes aberrant transport of EAAT3 to lysosome for catabolism and impairs 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 an explanation for upregulation of the receptor seen in surviving neurons of the human epileptic brain.