RT Journal Article
SR Electronic
T1 SorCS2 controls functional expression of amino acid transporter EAAT3 to protect neurons from oxidative stress and epilepsy-induced pathology
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 426734
DO 10.1101/426734
A1 Anna R. Malik
A1 Kinga Szydlowska
A1 Karolina Nizinska
A1 Antonino Asaro
A1 Erwin A. van Vliet
A1 Oliver Popp
A1 Gunnar Dittmar
A1 Anders Nykjaer
A1 Katarzyna Lukasiuk
A1 Eleonora Aronica
A1 Thomas E. Willnow
YR 2018
UL http://biorxiv.org/content/early/2018/09/25/426734.abstract
AB 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.