Willnow Lab

Introduction

SORCS1, -2, and -3 are three closely related VPS10P domain receptors genetically associated with glucose homeostasis and diabetes, as well as with AD (Fig. 1A). Earlier, we identified roles for these receptors in trophic signaling in the brain by directing the neurotrophin receptor TrkB to the neuronal cell surface, promoting neuronal survival (Glerup et al., Neuron 2014) and hypothalamic control of appetite (Subkhangulova et al., EMBO Reports 2018). Recently, we focused on studies that uncovered the significance of SORCS2 for neurodegenerative diseases.

SORCS2 is a stress response factor to protect from acute insults to the brain

In two separate studies, we applied stress paradigms, namely epilepsy and stroke, to WT and Sorcs2 KO mice to interrogate the relevance of SORCS2 for brain stress response. In Malik et al. (Cell Reports 2019), we show that SORCS2 acts as a 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 cysteine uptake. As a consequence, SORCS2 KO mice exhibit oxidative brain damage and increased mortality during epilepsy. We identified a similar protective function for SORCS2 during stroke (Malik et al., Glia 2020). Although primarily expressed in neurons in the healthy brain, SORCS2 expression is induced in astrocytes surrounding the ischemic core in WT mice following stroke. In astrocytes, SORCS2 induces the release of endostatin, a growth factor linked to post-stroke angiogenesis. Endostatin release from astrocytes is lost in SORCS2 KO mice, resulting in impaired vascularization of the ischemic brain.