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Cell Rep. 2019 Mar 5;26(10):2792-2804.e6. doi: 10.1016/j.celrep.2019.02.027.

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

Author information

1
Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany. Electronic address: anna.malik@mdc-berlin.de.
2
Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
3
Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
4
Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, the Netherlands; Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH, Amsterdam, the Netherlands.
5
Department of Oncology, Luxembourg Institute of Health, 1445 Strassen, Luxembourg.
6
Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany; Berlin Institute of Health Metabolomics Platform, 10178 Berlin, Germany.
7
MIND Center, Danish Research Institute of Translational Neuroscience - DANDRITE, The Danish Research Foundation Center PROMEMO, Departments of Biomedicine, Aarhus University, and Neurosurgery, Aarhus University Hospital, 8000C Aarhus, Denmark.
8
Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, the Netherlands; Stichting Epilepsie Instellingen Nederland (SEIN), 2103 SW Heemstede, the Netherlands.
9
Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany. Electronic address: willnow@mdc-berlin.de.

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:

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

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