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

Anna R. Malik, Kinga Szydlowska, Karolina Nizinska, Antonino Asaro, Erwin A. van Vliet, Oliver Popp, Gunnar Dittmar, Raphaela Fritsche-Guenther, Jennifer A. Kirwan, Anders Nykjaer, Katarzyna Lukasiuk, Eleonora Aronica, Thomas E. Willnow

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)2792-2804.e6
JournalCell Reports
Volume26
Issue number10
DOIs
Publication statusPublished - 5 Mar 2019
Externally publishedYes

Cite this

Malik, A. R., Szydlowska, K., Nizinska, K., Asaro, A., van Vliet, E. A., Popp, O., ... Willnow, T. E. (2019). SorCS2 Controls Functional Expression of Amino Acid Transporter EAAT3 and Protects Neurons from Oxidative Stress and Epilepsy-Induced Pathology. Cell Reports, 26(10), 2792-2804.e6. https://doi.org/10.1016/j.celrep.2019.02.027