| 2014 |
SorCS2 functions as a proneurotrophin (proNT) receptor that mediates both trophic and apoptotic signals in conjunction with p75NTR. In CNS neurons, SorCS2 exists as a single-chain protein required for proBDNF-induced growth cone collapse in developing dopaminergic processes. In PNS glia (Schwann cells), proteolytic processing produces a two-chain SorCS2 isoform that mediates proNT-dependent apoptosis; sciatic nerve injury triggers generation of two-chain SorCS2 in p75NTR-positive dying Schwann cells, with apoptosis profoundly attenuated in Sorcs2−/− mice. |
Knockout mouse phenotyping (Sorcs2−/− and p75NTR−/−), biochemical characterization of SorCS2 processing (single- vs two-chain isoforms), growth cone collapse assay, dopamine level measurements, behavioral assays |
Neuron |
High |
24908487
|
| 2016 |
SorCS2 forms complexes with p75NTR (static interaction) and with TrkB (activity-dependent interaction) in hippocampal neurons. The SorCS2-p75NTR complex is required for proBDNF-induced long-term depression, and the SorCS2-TrkB complex facilitates TrkB translocation to postsynaptic densities for synaptic tagging and maintenance of long-term potentiation. Neurons lacking SorCS2 fail to respond to BDNF by TrkB autophosphorylation and activation of downstream signaling cascades, impairing neurite outgrowth and spine formation. |
Co-immunoprecipitation, synaptic plasticity recordings (LTP/LTD) in Sorcs2−/− hippocampal slices, TrkB phosphorylation assays, subcellular fractionation, behavioral testing |
Molecular psychiatry |
High |
27457814
|
| 2018 |
Crystal structures of the SorCS2 ectodomain (unliganded and in complex with NGF) reveal cross-braced SorCS2 homodimers with two NGF dimers bound in a 2:4 stoichiometry. Five of six SorCS2 domains contribute to dimer formation; a C-terminal membrane-proximal domain with an RNA recognition motif fold locks the dimer in an intermolecular head-to-tail interaction. Both NGF dimer chains interact exclusively with the top face of the SorCS2 β-propeller, which serves as the ligand-binding platform. Biophysical experiments confirmed that NGF, proNGF, and proBDNF all bind at this β-propeller site. |
X-ray crystallography of SorCS2–NGF complex and unliganded SorCS2 ectodomain; biophysical binding experiments |
Nature communications |
High |
30061605
|
| 2019 |
SorCS2 acts as a sorting receptor that sustains cell-surface expression of the neuronal amino acid transporter EAAT3, facilitating cysteine import required for glutathione synthesis. Loss of SorCS2 depletes EAAT3 from the plasma membrane, impairs neuronal cysteine uptake, causes oxidative brain damage, and increases neuronal cell death and mortality during epilepsy. |
Surface biotinylation/fractionation to measure EAAT3 plasma membrane levels, cysteine uptake assays, oxidative stress markers, epilepsy survival assays in Sorcs2−/− mice |
Cell reports |
High |
30840898
|
| 2017 |
SorCS2 interacts with VPS35 (a core retromer component) and regulates surface trafficking of the NMDA receptor subunit NR2A in medium spiny neurons (MSNs) of the striatum. In zQ175 HD mice, SorCS2 is markedly decreased in an age- and allele-dependent manner and is mislocalized to perinuclear clusters. SorCS2 selectively interacts with mutant huntingtin (mtHTT) but not wild-type huntingtin. Genetic deficiency of SorCS2 accelerates onset and exacerbates motor coordination deficits in HD mice. |
Co-immunoprecipitation of SorCS2 with VPS35 and mtHTT, immunofluorescence localization, surface receptor analysis, behavioral testing in double-mutant mice |
JCI insight |
Medium |
28469074
|
| 2020 |
SorCS2 is a selective regulator of NMDA receptor (but not AMPA receptor) surface trafficking in hippocampal neurons, localizing to the postsynaptic density and endosomes within dendritic spines of CA2 neurons. SorCS2 deficiency reduces dendritic spine density in CA2 neurons and impairs social memory without affecting sociability or other hippocampal-dependent behaviors. |
Surface receptor trafficking assays (distinguishing NMDA vs AMPA), immunolocalization to postsynaptic density/endosomes, dendritic spine analysis, behavioral testing in novel Sorcs2−/− mice |
Molecular psychiatry |
High |
31988435
|
| 2020 |
In astrocytes surrounding ischemic brain injury, SorCS2 expression is induced by TGF-β1 and controls secretion of endostatin. Loss of SorCS2 in mice abolishes the acute post-stroke endostatin response and impairs vascularization of the ischemic brain, identifying SorCS2 as a sorting receptor for endostatin release from reactive astrocytes. |
Mouse stroke models (in vivo), TGF-β1 stimulation of astrocytes in vitro, endostatin secretion assays, vascularization quantification in Sorcs2−/− mice |
Glia |
Medium |
31898841
|
| 2017 |
Disruption of SorCS2 in mice causes severe stereociliary bundle defects in cochlear and vestibular macular hair cells. SorCS2 loss disrupts the intrinsic polarity pathway: LGN and Gαi3 were largely absent and aPKC lost its asymmetric distribution in affected hair cells, placing SorCS2 upstream of the intrinsic polarity pathway controlling hair bundle formation. |
Transgenic disruption of SorCS2 locus confirmed by whole-genome sequencing and qPCR; immunolabeling of polarity markers LGN, Gαi3, aPKC in cochlear/vestibular tissue; hair bundle morphology analysis |
PLoS genetics |
Medium |
28346477
|
| 2023 |
SorCS2 is a progranulin (PGRN) receptor required for motor neuron (MN) diversification and axon outgrowth. SorCS2 binds PGRN to control its secretion, intracellular signaling, and conversion into granulins. In zebrafish, SorCS2 knockdown impairs neuromuscular junction morphology and motility. In mice, SorCS2 deficiency perturbs cell-fate decisions of brachial MNs and slows adult motor nerve regeneration. Primitive macrophage-derived PGRN interacts with SorCS2-positive motor axons during pathfinding. |
Zebrafish knockdown (morpholino/CRISPR), mouse knockout analysis, co-expression studies, PGRN binding/secretion/processing assays, cell-fate tracing, nerve segmentation |
Cell reports |
High |
37897724
|
| 2023 |
SorCS2 undergoes alternative splicing that generates four variants differing in insertion of an acidic cluster motif and/or a serine residue in the intracellular domain (ICD), each undergoing proteolytic processing to give eight protein isoforms. Variants lacking the serine (but not those with it) rescued BDNF-induced neuronal branching in SorCS2 KO neurons. Variants without the acidic cluster show increased interactions with clathrin-associated adaptors AP-1, AP-2, and AP-3. Yeast two-hybrid screens revealed that all variants bound dynein light chain Tctex-type 3, but only variants with the acidic cluster motif bound kinesin light chain 1, giving variants distinct trafficking routes and subcellular localizations. |
Alternative splicing characterization, rescue assays in SorCS2 KO hippocampal neurons, co-immunoprecipitation with AP complexes, yeast two-hybrid screening for Tctex-type 3 and kinesin light chain 1, subcellular localization assays |
The Journal of biological chemistry |
High |
37507021
|
| 2023 |
SorCS2 is predominantly expressed in pancreatic islet alpha cells and controls osteopontin production/secretion; loss of SorCS2 prevents alpha cells from producing osteopontin, a secreted factor that facilitates insulin release from stressed beta cells, leading to defective insulin granule maturation and blunted glucose response in beta cells. |
Metabolic studies in SORCS2-deficient mice, ex vivo functional islet analyses, single-cell transcriptomics of pancreatic tissue, osteopontin secretion assays |
iScience |
Medium |
38226160
|
| 2021 |
Loss of SorCS2 in mice results in elevated DNA double-strand break (DSB) levels in the dentate gyrus. Knockout of SORCS2 in a human neuronal cell line increased Topoisomerase IIβ-dependent DSB formation and reduced neuronal viability, linking SorCS2 to regulation of DNA integrity via a Topoisomerase IIβ-dependent pathway. |
γH2AX immunostaining for DSBs in mouse dentate gyrus, SORCS2 CRISPR KO in human neuronal cell line, Topoisomerase IIβ inhibitor experiments, viability assays |
Cellular and molecular neurobiology |
Medium |
34741697
|
| 2025 |
The SorCS2 intracellular domain (ICD) contains a triple serine motif that functions as a signaling switch. Serine-to-alanine substitution renders neurons less responsive to BDNF, whereas phosphomimetic mutations induce neurotrophic effects independently of the SorCS2 extracellular domain and BDNF. Triple serine motif-based cell-penetrating peptides activate intracellular signaling that partially overlaps with the BDNF pathway and ultimately activates the transcription factor CREB. |
Site-directed mutagenesis (serine→alanine and phosphomimetic substitutions), BDNF response assays in hippocampal neurons, cell-penetrating peptide experiments, CREB activation assays |
iScience |
Medium |
40520096
|
| 2025 |
A heterozygous SORCS2 variant (arginine-to-tryptophan substitution in the 10CC region of the extracellular Vps10p domain) found in ADHD patients causes aberrant posttranslational receptor processing, altered subcellular localization, impaired ligand binding, and abrogates BDNF signaling in a dominant-negative manner. |
Biochemical characterization of variant processing (Western blot), subcellular localization assays, ligand binding assays, BDNF signaling assays in cells expressing the variant |
Molecular psychiatry |
Medium |
40968259
|
| 2025 |
SorCS2 is important for astrocytic neurovascular coupling. SorCS2 is strongly expressed in astrocyte endfeet at P8 but sparse in adult brain. Sorcs2−/− mice show reduced neurovascular coupling associated with reduced astrocytic calcium response to neuronal excitation. In Sorcs2−/− astrocytes, AQP4 abundance is increased in bulk lysate but reduced in the cell surface fraction, indicating impaired AQP4 trafficking; glutamate metabotropic receptor 3 (mGluR3) is also increased. |
Immunostaining for SorCS2/GFAP/AQP4, laser speckle contrast imaging for neurovascular coupling in vivo, calcium imaging in live brain slices, cell surface fraction proteomics, Western blot, qPCR |
Acta physiologica |
Medium |
40342271
|
| 2024 |
Hippocampal SorCS2 overexpression (via AAV) reverses chronic stress-induced depression-like behaviors in mice and restores SorCS2-TrkB binding, BDNF signaling cascade activation, and hippocampal neurogenesis. Chronic stress reduces SorCS2-TrkB complex formation specifically in the hippocampus. |
AAV-mediated SorCS2 overexpression in hippocampus of CSDS/CUMS mice, Co-IP of SorCS2-TrkB, BDNF pathway phosphorylation assays, immunofluorescence for immature neurons, behavioral testing |
Pharmacology, biochemistry, and behavior |
Medium |
38996926
|
| 2025 |
SorCS2-derived macrocyclic peptides (TT-P34) activate CREB and AMPK in a CAMKK2-dependent manner, upregulating PGC1α and TFEB and inducing mitochondrial biogenesis. In zQ175 HD mice, TT-P34 rescues motor behavioral deficits and preserves synaptic and mitochondrial signatures. In MPTP-induced Parkinson's Disease mice, TT-P34 ameliorates behavioral deficits and reduces dopaminergic loss. TT-P34 crosses the blood-brain barrier in non-human primates. |
Macrocyclic peptide design, CREB/AMPK/PGC1α/TFEB pathway assays, CAMKK2 inhibitor epistasis, behavioral testing in zQ175 and MPTP mouse models, non-human primate pharmacokinetics |
bioRxivpreprint |
Medium |
bio_10.1101_2025.09.17.676723
|