SorLA restricts TNFα release from microglia to shape a glioma-supportive brain microenvironment.

SorLA, encoded by the gene SORL1, is an intracellular sorting receptor of the VPS10P domain receptor gene family. Although SorLA is best recognized for its ability to shuttle target proteins between intracellular compartments in neurons, recent data suggest that also its microglial expression can be of high relevance for the pathogenesis of brain diseases, including glioblastoma (GBM). Here, we interrogated the impact of SorLA on the functional properties of glioma-associated microglia and macrophages (GAMs). In the GBM microenvironment, GAMs are re-programmed and lose the ability to elicit anti-tumor responses. Instead, they acquire a glioma-supporting phenotype, which is a key mechanism promoting glioma progression. Our re-analysis of published scRNA-seq data from GBM patients revealed that functional phenotypes of GAMs are linked to the level of SORL1 expression, which was further confirmed using in vitro models. Moreover, we demonstrate that SorLA restrains secretion of TNFα from microglia to restrict the inflammatory potential of these cells. Finally, we show that loss of SorLA exacerbates the pro-inflammatory response of microglia in the murine model of glioma and suppresses tumor growth.

SorCS2 binds progranulin to regulate motor neuron development.

Motor neuron (MN) development and nerve regeneration requires orchestrated action of a vast number of molecules. Here, we identify SorCS2 as a progranulin (PGRN) receptor that is required for MN diversification and axon outgrowth in zebrafish and mice. In zebrafish, SorCS2 knockdown also affects neuromuscular junction morphology and fish motility. In mice, SorCS2 and PGRN are co-expressed by newborn MNs from embryonic day 9.5 until adulthood. Using cell-fate tracing and nerve segmentation, we find that SorCS2 deficiency perturbs cell-fate decisions of brachial MNs accompanied by innervation deficits of posterior nerves. Additionally, adult SorCS2 knockout mice display slower motor nerve regeneration. Interestingly, primitive macrophages express high levels of PGRN, and their interaction with SorCS2-positive motor axon is required during axon pathfinding. We further show that SorCS2 binds PGRN to control its secretion, signaling, and conversion into granulins. We propose that PGRN-SorCS2 signaling controls MN development and regeneration in vertebrates.

SORLA mediates endocytic uptake of proIAPP and protects against islet amyloid deposition.

OBJECTIVE: Sorting-related receptor with type A repeats (SORLA) is a neuronal sorting receptor that prevents accumulation of amyloid-beta peptides, the main constituent of senile plaques in Alzheimer disease. Recent transcriptomic studies show that SORLA transcripts are also found in beta cells of pancreatic islets, yet the role of SORLA in islets is unknown. Based on its protective role in reducing the amyloid burden in the brain, we hypothesized that SORLA has a similar function in the pancreas via regulation of amyloid formation from islet amyloid polypeptide (IAPP). METHODS: We generated human IAPP transgenic mice lacking SORLA (hIAPP:SORLA KO) to assess the consequences of receptor deficiency for islet histopathology and function in vivo. Using both primary islet cells and cell lines, we further investigated the molecular mechanisms whereby SORLA controls the cellular metabolism and accumulation of IAPP. RESULTS: Loss of SORLA activity in hIAPP:SORLA KO resulted in a significant increase in islet amyloid deposits and associated islet cell death compared to hIAPP:SORLA WT animals. Aggravated islet amyloid deposition was observed in mice fed a normal chow diet, not requiring high-fat diet feeding typically needed to induce islet amyloidosis in mouse models. In vitro studies showed that SORLA binds to and mediates the endocytic uptake of proIAPP, but not mature IAPP, delivering the propeptide to an endolysosomal fate. CONCLUSIONS: SORLA functions as a proIAPP-specific clearance receptor, protecting against islet amyloid deposition and associated cell death caused by IAPP.

Intraneuronal sortilin aggregation relative to granulovacuolar degeneration, tau pathogenesis and sorfra plaque formation in human hippocampal formation.

Extracellular ß-amyloid (Aß) deposition and intraneuronal phosphorylated-tau (pTau) accumulation are the hallmark lesions of Alzheimer's disease (AD). Recently, "sorfra" plaques, named for the extracellular deposition of sortilin c-terminal fragments, are reported as a new AD-related proteopathy, which develop in the human cerebrum resembling the spatiotemporal trajectory of tauopathy. Here, we identified intraneuronal sortilin aggregation as a change related to the development of granulovacuolar degeneration (GVD), tauopathy, and sorfra plaques in the human hippocampal formation. Intraneuronal sortilin aggregation occurred as cytoplasmic inclusions among the pyramidal neurons, co-labeled by antibodies to the extracellular domain and intracellular C-terminal of sortilin. They existed infrequently in the brains of adults, while their density as quantified in the subiculum/CA1 areas increased in the brains from elderly lacking Aß/pTau, with pTau (i.e., primary age-related tauopathy, PART cases), and with Aß/pTau (probably/definitive AD, pAD/AD cases) pathologies. In PART and pAD/AD cases, the intraneuronal sortilin aggregates colocalized partially with various GVD markers including casein kinase 1 delta (Ck1δ) and charged multivesicular body protein 2B (CHMP2B). Single-cell densitometry established an inverse correlation between sortilin immunoreactivity and that of Ck1δ, CHMP2B, p62, and pTau among pyramidal neurons. In pAD/AD cases, the sortilin aggregates were reduced in density as moving from the subiculum to CA subregions, wherein sorfra plaques became fewer and absent. Taken together, we consider intraneuronal sortilin aggregation an aging/stress-related change implicating protein sorting deficit, which can activate protein clearance responses including via enhanced phosphorylation and hydrolysis, thereby promoting GVD, sorfra, and Tau pathogenesis, and ultimately, neuronal destruction and death.

The adaptor protein PICK1 targets the sorting receptor SorLA.

SorLA is a member of the Vps10p-domain (Vps10p-D) receptor family of type-I transmembrane proteins conveying neuronal endosomal sorting. The extracellular/luminal moiety of SorLA has a unique mosaic domain composition and interacts with a large number of different and partially unrelated ligands, including the amyloid precursor protein as well as amyloid-ß. Several studies support a strong association of SorLA with sporadic and familial forms of Alzheimer's disease (AD). Although SorLA seems to be an important factor in AD, the large number of different ligands suggests a role as a neuronal multifunctional receptor with additional intracellular sorting capacities. Therefore, understanding the determinants of SorLA's subcellular targeting might be pertinent for understanding neuronal endosomal sorting mechanisms in general. A number of cytosolic adaptor proteins have already been demonstrated to determine intracellular trafficking of SorLA. Most of these adaptors and several ligands of the extracellular/luminal moiety are shared with the Vps10p-D receptor Sortilin. Although SorLA and Sortilin show both a predominant intracellular and endosomal localization, they are targeted to different endosomal compartments. Thus, independent adaptor proteins may convey their differential endosomal targeting. Here, we hypothesized that Sortilin and SorLA interact with the cytosolic adaptors PSD95 and PICK1 which have been shown to bind the Vps10p-D receptor SorCS3. We observed only an interaction for SorLA and PICK1 in mammalian-two-hybrid, pull-down and cellular recruitment experiments. We demonstrate by mutational analysis that the C-terminal minimal PDZ domain binding motif VIA of SorLA mediates the interaction. Moreover, we show co-localization of SorLA and PICK1 at vesicular structures in primary neurons. Although the physiological role of the interaction between PICK1 and SorLA remains unsolved, our study suggests that PICK1 partakes in regulating SorLA's intracellular itinerary.

ApoE4 disrupts interaction of sortilin with fatty acid-binding protein 7 essential to promote lipid signaling.

Sortilin is a neuronal receptor for apolipoprotein E (apoE). Sortilin-dependent uptake of lipidated apoE promotes conversion of polyunsaturated fatty acids (PUFA) into neuromodulators that induce anti-inflammatory gene expression in the brain. This neuroprotective pathway works with the apoE3 variant but is lost with the apoE4 variant, the main risk factor for Alzheimer's disease (AD). Here, we elucidated steps in cellular handling of lipids through sortilin, and why they are disrupted by apoE4. Combining unbiased proteome screens with analyses in mouse models, we uncover interaction of sortilin with fatty acid-binding protein 7 (FABP7), the intracellular carrier for PUFA in the brain. In the presence of apoE3, sortilin promotes functional expression of FABP7 and its ability to elicit lipid-dependent gene transcription. By contrast, apoE4 binding blocks sortilin-mediated sorting, causing catabolism of FABP7 and impairing lipid signaling. Reduced FABP7 levels in the brain of AD patients expressing apoE4 substantiate the relevance of these interactions for neuronal lipid homeostasis. Taken together, we document interaction of sortilin with mediators of extracellular and intracellular lipid transport that provides a mechanistic explanation for loss of a neuroprotective lipid metabolism in AD.

Elevation of CSF Sortilin Following Subarachnoid Hemorrhage in Patients and Experimental Model Rats.

Subarachnoid hemorrhage (SAH) can cause acute neuronal injury and chronic neurocognitive deficits; biomarkers reflecting its associated neuronal injury are of potential prognostic value. Sortilin, a member of the vacuolar protein sorting 10p (Vps10p) family, is enriched in neurons and is likely involved in neurodegenerative diseases. Here, we explored sortilin in the cerebrospinal fluid (CSF) as a potential biomarker for early neuronal injury after SAH. Sortilin levels in the CSF of SAH patients (n = 11) and controls (n = 6) were analyzed by immunoblot. SAH rats surviving 3-72 h (h) were evaluated neurologically, with their brain and CSF samples examined histologically and biochemically. Sortilin protein ~100 kDa was detected in the CSF from SAH patients only, with its levels correlated to Hunt-Hess scale. Rats in the SAH groups showed poorer Garcia score and beam balancing capability than sham controls. Sortilin ~100 kDa was detectable in the CSF of the SAH, but not sham, animals. Levels of sortilin ~100 kDa and fragments ~40 kDa in cortical lysates were elevated in the SAH relative to control rats. Levels of cortical glial fibrillary acidic protein (GFAP) were also elevated in the SAH rats. In immunohistochemistry, the pattern of sortilin labeling in the brain was largely comparable between the SAH and control rats, whereas an increased astrocytic GFAP immunolabeling was evident in the former. Together, these results suggest that SAH can cause an early and remarkable rise of sortilin products in CSF, likely reflecting neuronal change. Sortilin could be further explored as a potential biomarker in some brain disorders.

Apolipoprotein E4 disrupts the neuroprotective action of sortilin in neuronal lipid metabolism and endocannabinoid signaling.

INTRODUCTION: Apolipoprotein E (apoE) is a carrier for brain lipids and the most important genetic risk factor for Alzheimer's disease (AD). ApoE binds the receptor sortilin, which mediates uptake of apoE-bound cargo into neurons. The significance of this uptake route for brain lipid homeostasis and AD risk seen with apoE4, but not apoE3, remains unresolved. METHODS: Combining neurolipidomics in patient specimens with functional studies in mouse models, we interrogated apoE isoform-specific functions for sortilin in brain lipid metabolism and AD. RESULTS: Sortilin directs the uptake and conversion of polyunsaturated fatty acids into endocannabinoids, lipid-based neurotransmitters that act through nuclear receptors to sustain neuroprotective gene expression in the brain. This sortilin function requires apoE3, but is disrupted by binding of apoE4, compromising neuronal endocannabinoid metabolism and action. DISCUSSION: We uncovered the significance of neuronal apoE receptor sortilin in facilitating neuroprotective actions of brain lipids, and its relevance for AD risk seen with apoE4.

Extracellular Sortilin Proteopathy Relative to ß-Amyloid and Tau in Aged and Alzheimer's Disease Human Brains.

Amyloid plaques and neurofibrillary tangles (NFTs) are hallmark lesions of Alzheimer's disease (AD) related to ß-amyloid (Aß) deposition and intraneuronal phosphorylated tau (pTau) accumulation. Sortilin C-terminal fragments (shortened as "sorfra") can deposit as senile plaque-like lesions within AD brains. The course and pattern of sorfra plaque formation relative to Aß and pTau pathogenesis remain unknown. In the present study, cerebral and subcortical sections in postmortem human brains (n = 46) from aged and AD subjects were stained using multiple markers (6E10, ß-secretase 1, pTau, and sortilin antibodies, as well as Bielschowsky silver stain). The course and pattern of sorfra plaque formation relative to Thal Aß and Braak NFT pathogenic stages were determined. Sorfra plaques occurred in the temporal, inferior frontal and occipital neocortices in cases with Thal 1 and Braak III stages. They were also found additionally in the hippocampal formation, amygdala, and associative neocortex in cases with Thal 2-4 and Braak IV-V. Lastly, they were also found in the primary motor, somatosensory, and visual cortices in cases with Thal 4-5 and Braak VI. Unlike Aß and pTau pathologies, sorfra plaques did not occur in subcortical structures in cases with Aß/pTau lesions in Thal 3-5/Braak IV-VI stages. We establish here that sorfra plaques are essentially a cerebral proteopathy. We believe that the development of sorfra plaques in both cortical and hippocampal regions proceeds in a typical spatiotemporal pattern, and the stages of cerebral sorfra plaque formation partially overlap with that of Aß and pTau pathologies.

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

SorCS2 is an intracellular sorting receptor of the VPS10P domain receptor gene family recently implicated in oxidative stress response. Here, we interrogated the relevance of stress-related activities of SorCS2 in the brain by exploring its role in ischemic stroke in mouse models and in patients. Although primarily seen in neurons in the healthy brain, expression of SorCS2 was massively induced in astrocytes surrounding the ischemic core in mice following stroke. Post-stroke induction was likely a result of increased levels of transforming growth factor ß1 in damaged brain tissue, inducing Sorcs2 gene transcription in astrocytes but not neurons. Induced astrocytic expression of SorCS2 was also seen in stroke patients, substantiating the clinical relevance of this observation. In astrocytes in vitro and in the mouse brain in vivo, SorCS2 specifically controlled release of endostatin, a factor linked to post-stroke angiogenesis. The ability of astrocytes to release endostatin acutely after stroke was lost in mice deficient for SorCS2, resulting in a blunted endostatin response which coincided with impaired vascularization of the ischemic brain. Our findings identified activated astrocytes as a source for endostatin in modulation of post-stroke angiogenesis, and the importance of the sorting receptor SorCS2 in this brain stress response.

Reduced Alcohol Seeking and Withdrawal Symptoms in Mice Lacking the BDNF Receptor SorCS2.

Alcohol use disorder (AUD) is characterized by repetitive and uncontrolled intake of alcohol with severe consequences for affected individuals, their families and society as a whole. Numerous studies have implicated brain-derived neurotrophic factor (BDNF) activity in the neurobiology underlying AUD. The BDNF signaling mechanism is complex and depends on two receptor systems, TrkB and p75NTR, which appear to have opposite effects on alcohol seeking behavior in animal models. We recently discovered that the sortilin-related receptor SorCS2 forms complexes with both TrkB and p75NTR and is important for BDNF activity in the developing and adult CNS. Moreover, the SORCS2 gene was recently identified as the top association signal for severity of alcohol withdrawal symptoms. Hence, we speculated that SorCS2 deficient mice would have an altered response to alcohol. The role of SorCS2 in the acute and adapted response to alcohol was therefore investigated by comparing SorCS2 knockout (Sorcs2-/- ) mice to wild type (WT) mice in three paradigms modeling alcohol sensitivity and consumption; alcohol-induced conditioned place preference, two-bottle choice test as well as the behavioral response to alcohol withdrawal. We found that, when compared to the WT mice, (I) Sorcs2-/- mice displayed complete lack of alcohol-induced place preference, (II) when given free choice between water and alcohol, Sorcs2-/- mice consumed less alcohol, and (III) Sorcs2-/- mice showed no handling-induced convulsion in response to alcohol withdrawal following extended alcohol exposure. Taken together, these results show that lack of the alcohol withdrawal risk gene Sorcs2 results in abnormal behavioral response to alcohol in mice. Consequently, SorCS2 may play an important role in the molecular pathways underlying AUD and complications associated with alcohol withdrawal.

Amyloidosis causes downregulation of SorLA, SorCS1 and SorCS3 expression in mice.

Accumulation of ß-amyloid peptide (Aß) is regarded as a primary cause of Alzheimer's disease (AD). Aß is derived by sequential cleavage of the amyloid precursor protein (APP). Alterations in the subcellular targeting of APP are thought to affect the degree of Aß production. Sorting receptors, such as SorLA, convey subcellular targeting of APP. Dysfunction of SorLA, and likely of the related receptors SorCS1 and SorCS3, cause AD. Nevertheless, disease progression could also provoke altered expression of the receptors. Here, we assessed if Aß plaque formation promotes altered expression of SorLA, SorCS1 and SorCS3. We analyzed transcript levels during aging and after amyloidosis in brain areas characterized by early amyloid plaque formation in an AD mouse model (APPPS1) and wild types. We observed stable expression levels during aging (1-12 months). After plaque formation, SorCS1 and SorLA expression were markedly reduced in the frontal cerebral cortex and to a minor extent in the hippocampus, whereas SorCS3 expression was solely reduced in the frontal cerebral cortex. Our results indicate that disease progression, associated with Aß accumulation, can negatively regulate expression of the receptors.

Regional and Cellular Mapping of Sortilin Immunoreactivity in Adult Human Brain.

Sortilin is a member of the vacuolar protein sorting 10 protein (VPS10P) domain receptor family, which carries out signal transduction and protein transport in cells. Sortilin serves as the third, G-protein uncoupled, receptor of neurotensin that can modulate various brain functions. More recent data indicate an involvement of sortilin in mood disorders, dementia and Alzheimer-type neuropathology. However, data regarding the normal pattern of regional and cellular expression of sortilin in the human brain are not available to date. Using postmortem adult human brains free of neuropathology, the current study determined sortilin immunoreactivity (IR) across the entire brain. Sortilin IR was broadly present in the cerebrum and subcortical structures, localizing to neurons in the somatodendritic compartment, but not to glial cells. In the cerebrum, sortilin IR exhibited differential regional and laminar patterns, with pyramidal, multipolar and polymorphic neurons in cortical layers II-VI, hippocampal formation and amygdaloid complex more distinctly labeled relative to GABAergic interneurons. In the striatum and thalamus, numerous small-to-medium sized neurons showed light IR, with a small group of large sized neurons heavily labeled. In the midbrain and brainstem, sortilin IR was distinct in neurons at the relay centers of descending and ascending neuroanatomical pathways. Dopaminergic neurons in the substantia nigra, cholinergic neurons in the basal nuclei of Meynert and noradrenergic neurons in the locus coeruleus co-expressed strong sortilin IR in double immunofluorescence. In comparison, sortilin IR was weak in the olfactory bulb and cerebellar cortex, with the mitral and Purkinje cells barely visualized. A quantitative analysis was carried out in the lateral, basolateral, and basomedial nuclei of the amygdaloid complex, as well as cortical layers II-VI, which established a positive correlation between the somal size and the intensity of sortilin IR among labeled neurons. Together, the present study demonstrates a predominantly neuronal expression of sortilin in the human brain with substantial regional and cell-type variability. The enriched expression of sortilin in pyramidal, dopaminergic, noradrenergic and cholinergic neurons suggests that this protein may be particularly required for signal transduction, protein trafficking and metabolic homeostasis in populations of relatively large-sized projective neurons.

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

VPS10P 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.

Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer's disease model mice and macaques.

BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disorder bearing multiple pathological hallmarks suggestive of complex cellular/molecular interplay during pathogenesis. Transgenic mice and nonhuman primates are used as disease models for mechanistic and translational research into AD; the extent to which these animal models recapitulate AD-type neuropathology is an issue of importance. Putative C-terminal fragments from sortilin, a member of the vacuolar protein sorting 10 protein (Vps10p) family, have recently been shown to deposit in the neuritic ß-amyloid (Aß) plaques in the human brain. METHODS: We set out to explore if extracellular sortilin neuropathology exists in AD-related transgenic mice and nonhuman primates. Brains from different transgenic strains and ages developed overt cerebral Aß deposition, including the ß-amyloid precursor protein and presenilin 1 double-transgenic (APP/PS1) mice at ~ 14 months of age, the five familial Alzheimer's disease mutations transgenic (5×FAD) mice at ~ 8 months, the triple-transgenic Alzheimer's disease (3×Tg-AD) mice at ~ 22 months, and aged monkeys (Macaca mulatta and Macaca fascicularis) were examined. Brain samples from young transgenic mice, middle-aged/aged monkeys, and AD humans were used as negative and positive pathological controls. RESULTS: The C-terminal sortilin antibody, which labeled senile plaques in the AD human cerebral sections, did not display extracellular immunolabeling in the transgenic mouse or aged monkey brain sections with Aß deposition. In Western blot analysis, sortilin fragments ~ 15 kDa were not detectable in transgenic mouse cortical lysates, but they occurred in control AD lysates. CONCLUSIONS: In reference to their human brain counterparts, neuritic plaques seen in transgenic AD model mouse brains represent an incomplete form of this AD pathological hallmark. The species difference in neuritic plaque constituents also indicates more complex secondary proteopathies in the human brain relative to rodents and nonhuman primates during aging and in AD.

Sortilin: a new player in dementia and Alzheimer-type neuropathology.

Age-related dementias are now a major mortality factor among most human populations in the world, with Alzheimer's disease (AD) being the leading dementia-causing neurodegenerative disease. The pathogenic mechanism underlying dementia disorders, and AD in particular, remained largely unknown. Efforts to develop drugs targeting the disease's hallmark lesions, such as amyloid plaque and tangle pathologies, have been unsuccessful so far. The vacuolar protein sorting 10p (Vps10p) family plays a critical role in membrane signal transduction and protein sorting and trafficking between intracellular compartments. Data emerging during the past few years point to an involvement of this family in the development of AD. Specifically, the Vps10p member sortilin has been shown to participate in amyloid plaque formation, tau phosphorylation, abnormal protein sorting and apoptosis. In this minireview, we update some latest findings from animal experiments and human brain studies suggesting that abnormal sortilin expression is associated with AD-type neuropathology, warranting further research that might lead to novel targets for the development of AD therapies.

SORCS1 and SORCS3 control energy balance and orexigenic peptide production.

SORCS1 and SORCS3 are two related sorting receptors expressed in neurons of the arcuate nucleus of the hypothalamus. Using mouse models with individual or dual receptor deficiencies, we document a previously unknown function of these receptors in central control of metabolism. Specifically, SORCS1 and SORCS3 act as intracellular trafficking receptors for tropomyosin-related kinase B to attenuate signaling by brain-derived neurotrophic factor, a potent regulator of energy homeostasis. Loss of the joint action of SORCS1 and SORCS3 in mutant mice results in excessive production of the orexigenic neuropeptide agouti-related peptide and in a state of chronic energy excess characterized by enhanced food intake, decreased locomotor activity, diminished usage of lipids as metabolic fuel, and increased adiposity, albeit at overall reduced body weight. Our findings highlight a novel concept in regulation of the melanocortin system and the role played by trafficking receptors SORCS1 and SORCS3 in this process.

Novel amplification mechanism of prions through disrupting sortilin-mediated trafficking.

Conformational conversion of the cellular prion protein, PrPC, into the abnormally folded isoform of prion protein, PrPSc, which leads to marked accumulation of PrPSc in brains, is a key pathogenic event in prion diseases, a group of fatal neurodegenerative disorders caused by prions. However, the exact mechanism of PrPSc accumulation in prion-infected neurons remains unknown. We recently reported a novel cellular mechanism to support PrPSc accumulation in prion-infected neurons, in which PrPSc itself promotes its accumulation by evading the cellular inhibitory mechanism, which is newly identified in our recent study. We showed that the VPS10P sorting receptor sortilin negatively regulates PrPSc accumulation in prion-infected neurons, by interacting with PrPC and PrPSc and trafficking them to lysosomes for degradation. However, PrPSc stimulated lysosomal degradation of sortilin, disrupting the sortilin-mediated degradation of PrPC and PrPSc and eventually evoking further accumulation of PrPSc in prion-infected neurons. These findings suggest a positive feedback amplification mechanism for PrPSc accumulation in prion-infected neurons.

Acidic Environment Induces Dimerization and Ligand Binding Site Collapse in the Vps10p Domain of Sortilin.

Sortilin is a neuronal receptor involved in transmembrane signaling, endocytosis, and intracellular sorting of proteins. It cycles through a number of cellular compartments where it encounters various acidic conditions. The crystal structure of the sortilin ectodomain has previously been determined at neutral pH. Here, we present the 3.5-Å resolution crystal structure of sortilin at pH 5.5, which represents an environment similar to that of late endosomes, where ligands are released. The structure reveals an overall distortion of the 10-bladed ß-propeller domain. This distortion and specific conformational changes, caused by protonation of a number of histidine residues, render the currently known binding sites unavailable for ligand binding. Access to the binding sites is furthermore blocked by a reversible and pH-dependent formation of tight sortilin dimers, also confirmed by electron microscopy, size-exclusion chromatography, and mutational studies. This study reveals how sortilin binding sites are disrupted and explains pH-dependent ligand affinity.

Hidden Twins: SorCS Neuroreceptors Form Stable Dimers.

SorCS1, SorCS2 and SorCS3 belong to the Vps10p-domain family of multiligand receptors. Genetic and functional studies have linked SorCS receptors to psychiatric disorders, Alzheimer's disease and type 2 diabetes, demonstrating critical roles in neuronal functionality and metabolic control. Surprisingly, their structural composition has so far not been studied. Here we have characterized SorCS1, SorCS2 and SorCS3 using biochemical methods and electron microscopy. We found that their purified extracellular domains co-exist in stable dimeric and monomeric populations. This was supported by co-immunoprecipitation experiments, where membrane-bound dimers were successfully pulled down from cell lysate. While dimers were virtually unbreakable, dimerization of the monomeric population was promoted through enzymatic deglycosylation. We conclude that post-translational modifications, specifically the degree and pattern of glycosylation, regulate the oligomeric state of the protein. Hence, cells may dictate ligand specificity by controlling the ratio between monomers and dimers and, therefore, regulate the multiple functions of SorCS receptors.