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

Abstract

SummaryVPS10P 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.

SorCS1-mediated sorting in dendrites maintains neurexin axonal surface polarization required for synaptic function

“…Our results show that loss of SorCS1 impairs transcytotic trafficking of Nrxn and L1/NgCAM, but not of Caspr2, which traffics via the selective endocytosis/retention pathway, supporting a role for SorCS1 in regulating transcytotic trafficking of axonal cargo proteins. It is unlikely that all membrane proteins that have been identified using surface proteome analysis to depend on SorCS1-3 for their surface trafficking [20,23,24] undergo transcytosis. The SorCS1 cargo amyloid precursor protein (APP) [50–52], however, is transcytosed in human neurons [53].…”

“…The vertebrate Sortilin-related CNS expressed 1–3 (SorCS1-3) proteins are sorting receptors belonging to the vacuolar protein sorting 10 (VPS10P) family receptors that have emerged as major regulators of intracellular protein trafficking [18,19]. SorCS proteins are required for the surface expression of glutamate receptors, neurotrophin receptors, transporters, and adhesion molecules [20–24]. These sorting receptors are thus essential for synaptic transmission and plasticity, but the mechanisms by which SorCS proteins sort their cargo are poorly understood.…”

LAMA4-Regulating miR-4274 and Its Host Gene SORCS2 Play a Role in IGFBP6-Dependent Effects on Phenotype of Basal-Like Breast Cancer

“…Interestingly, gene variant located in a vicinity of SORCS2 (rs4234798) demonstrated genome-wide significant associations with circulating concentrations of IGFBP-3 and IGF-I (Kaplan et al, 2011; Teumer et al, 2016), previously described as a prognostic marker in basal-like triple-negative breast cancer (Marzec et al, 2015; Julovi et al, 2018), and as a part of 19-gene expression signature which substantially outperforms Dukes' classification predicting the survival of patients with colorectal cancer (Aziz et al, 2016). Protein encoded by SORCS2 gene coordinates intracellular transport of the glutamate and cysteine transporter EAAT3 (Malik et al, 2019) in the neurons, where it provides a degree of protection from oxidative stress and epilepsy-induced cell death (Shkurnikov et al, 2013). Given that expression of SORCS2 mRNA is highly restricted to the nervous system and the kidneys, it is tempting to speculate that the function of relatively high levels of SORCS2 expression observed in basal-like breast carcinomas should be attributed to intragenic miRNA hsa-miR-4274.…”

SorCS2 facilitates release of endostatin from astrocytes and controls post‐stroke angiogenesis

“…Neuronal cultures were prepared from hippocampi and cortices of newborn mice as described earlier (Malik et al, ). In brief, cultures were prepared using enzymatic digestion with papain and plated at the density of 83,000 cells/cm 2 .…”

“…Recently, we documented that SorCS2 is unique among the various VPS10P domain receptors as its expression is up‐regulated in response to oxidative stress and epilepsy in neurons (Malik et al, ). Under these conditions, SorCS2 promotes cell surface sorting of the neuronal amino acid transporter EAAT3, facilitating EAAT3‐mediated uptake of cysteine for production of the reactive oxygen species scavenger glutathione (Malik et al, ). Ultimately, induced expression of SorCS2 enables neurons to cope with oxidative stress and protects them from seizure‐induced cell death.…”