SORCS2 is a member of the Vps10p-domain receptor family, which comprises five multifunctional neuronal receptors, type I transmembrane receptors Sortilin in humans or sortilin in mice (encoded by the gene SORT1 or Sort1, respectively), SORLA/SorLA (encoded by SORL1/Sorl1) and SORCS1-3/SorCS1-3 (encoded by SORCS1- 3/Sorcs1-3)^{1, 2}. The receptor family is expressed predominantly in the nervous system (both developing and adult) and involved in intracellular sorting and trafficking of various neurotrophic factors and their precursor forms, as well transmembrane receptors and synaptic proteins¹.

This gene family has been implicated in a broad range of cellular processes, including neuronal health, differentiation and synaptic plasticity^{1, 2}. The SorCS subfamily contains three closely related members, with at least 49% identity between the VPS10 domains³. SorCS members also contain a leucine rich region (LRR), with 63% identity between SorCS1 and SorCS3 versus only 35% identity between SorCS1 and SorCS2³. The three SorCS genes are differentially expressed and regulated in mature neurons³.

Since their discovery a growing number of studies have linked SorCS genes to diverse neurodegenerative diseases such as autism, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, late-onset Alzheimer disease and multiple sclerosis^4-6. SorCS2 is the VPS10 family member that is the least characterized. Ten years after its identification⁷, a first role for SorCS2 in proneurotrophin-mediated neurodegeneration as co-receptor of the p75NTR was uncovered⁸. Roles for SorCS2 in amyotrophic lateral sclerosis, bipolar disorder and schizophrenia have been suggested^{5, 6, 9}, but the mechanism of action of SorCS2 is poorly understood¹⁰, though recent studies have shown that SorCS2 regulates pro-BDNF dependent synapse plasticity^{11, 12}. Furthermore, SorCS2 has been linked to obesity and colorectal cancer, suggesting a role akin to Sortilin’s for SorCS2 in these diseases^13-15.

SorCS2 is localized predominantly in the brain, but also in heart, liver and kidney^{7, 16}. Unlike Sortilin, SorCS2 is preferentially located at the cell surface in mature neurons of the central nervous system (CNS) and glia of the peripheral nervous system (PNS), making it the preferred co-receptor for p75-dependent apoptosis¹⁷. SorCS2 contains a leucine-rich region linking the VPS10 domain and the transmembrane domain. It has been shown to exist both as a single chain receptor in the neurons of the CNS and as a cleaved two-chains receptor in the glia of the PNS¹⁸. The proteolytic processing site yielding this two-chain version of SorCS2 is located in the leucine-rich region at residue S1031. SorCS2 interacts with proneurotrophins^{8, 11, 12}. Both single and double-chain SorCS2 interact with proneurotrophins (and with less affinity to mature neurotrophins) and form a ternary complex with p75NTR, but the single chain receptor induces growth cone collapse of dopaminergic neurons while the double-chain receptor transduces apoptosis signals in PNS glia¹⁸.