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

*Corresponding author for this work

    Research output: Contribution to journalArticleResearchpeer-review

    33 Citations (Scopus)

    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

    Keywords

    • EAAC1
    • EAAT3
    • VPS10P domain receptors
    • epilepsy
    • glutathione
    • intracellular protein sorting
    • oxidative stress

    Fingerprint

    Dive into the research topics of 'SorCS2 Controls Functional Expression of Amino Acid Transporter EAAT3 and Protects Neurons from Oxidative Stress and Epilepsy-Induced Pathology'. Together they form a unique fingerprint.

    Cite this