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

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Item Type:Article
Title:SorCS2 controls functional expression of amino acid transporter EAAT3 and protects neurons from oxidative stress and epilepsy-induced pathology
Creators Name:Malik, A.R. and Szydlowska, K. and Nizinska, K. and Asaro, A. and van Vliet, E.A. and Popp, O. and Dittmar, G. and Fritsche-Guenther, R. and Kirwan, J.A. and Nykjaer, A. and Lukasiuk, K. and Aronica, E. and Willnow, T.E.
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.
Keywords:VPS10P Domain Receptors, Intracellular Protein Sorting, Oxidative Stress, EAAT3, EAAC1, Epilepsy, Glutathione, Animals, Mice
Source:Cell Reports
ISSN:2211-1247
Publisher:Cell Press / Elsevier (U.S.A.)
Volume:26
Number:10
Page Range:2792-2804
Date:5 March 2019
Official Publication:https://doi.org/10.1016/j.celrep.2019.02.027
PubMed:View item in PubMed
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https://edoc.mdc-berlin.de/17968/Preprint version

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