SORCS1 (also known as Sortilin-Related VPS10 Domain Containing Receptor 1, VPS10 Domain-Containing Receptor) is a member of the vacuolar protein sorting 10 protein (VPS10p) domain receptor family.

VPS10p domain receptor (VPS10p-D) family comprises five type-1 transmembrane proteins: SorCS1, SorCS2, SorCS3, SorLA and Sortilin. These receptors carry an extracellular 700 amino acid VPS10p domain that serves as a ligand binding site. Ligands for VPS10p-D receptors include transmembrane proteins, such as signaling receptors and transporters, as well as secreted factors, including trophic factors and morphogens. They also bind synaptic components, in particular pro- and mature neurotrophins and their respective receptors, thus controlling synaptic plasticity, synaptogenesis and cell fate decisions. VPS10p-D receptors act by two different signaling modalities; they control signal transduction at the cell membrane, and they sort multiple types of cargoes by endocytosis and intracellular trafficking, targeting them to distinct cellular compartments. They shuttle between early endosomes and trans golgi network (TGN), sorting cargo between these compartments. Dysfunction in their sorting pathway typically causes cytotoxic protein aggregation and altered cell signaling.

SORCS1 is present in the soma, dendritic vesicles, and at the plasma membrane of neurons. Its expression is dynamic and can be regulated by synaptic activity. It is mainly expressed in neurons from cerebral cortex, amygdala, hippocampus, and thalamus. It is also expressed in adult liver, pancreas, kidney, and heart. All SorCS proteins are mutually highly homologous and contain a leucine-rich domain that modulates protein–protein interactions. They differ in their short cytoplasmic tail (10–78 amino acids) that interacts with adaptor proteins to control intracellular trafficking. SorCS1 is unique as it exists in at least five isoforms, SorCS1a-e, that vary in their cytoplasmic tails and in their expression pattern. SorCS1 forms homodimers as well as heterodimers with SorCS2 and 3. Its intracellular transport is regulated by the retromer complex that controls transport out of the endosomal compartment.

SorCS1 binds and regulates multiple sorting proteins; by binding to Sortilin, it substantially reduces Sortilin's ability to mediate cellular uptake of its ligands and support signaling. In addition, SorCS1 knockout mice have been shown to exhibit decreased expression of SorLA and VPS35, the core protein of the retromer in the brain.^1,2

Based on several GWAS studies, VPS10p-D receptors are involved in the etiology of a number of neurological and psychiatric disorders including Alzheimer's disease (AD) and frontotemporal dementia. Specifically, SorCS1 participates in amyloid precursor protein (APP) trafficking and processing and interacts with other canonical AD proteins including Aβ, secretases, and ApoE. Expression of SorCS1 has been shown to predominantly decrease in the diseased brains.¹

SorCS1 was also identified as a type 2 diabetes quantitative trait locus in mice, and variations in the human gene are associated with diabetes-related traits.³ In a DNA methylation study in colorectal cancer (CRC), SorCS1 was hypermethylated and its expression was repressed by promoter methylation. In survival analysis, low SorCS1 expression level correlated with poorer outcomes of CRC patients, marking it as a possible tumor suppressor protein.⁴