Biology subjects

Vaegter, C. B.

Publications and source records attributed to Vaegter, C. B..

12 recordsLinked to original sources

bioRxiv2026

Antidepressants interact with sex steroid receptors and their intracellular signaling components

There is growing interest in understanding how hormonal signaling pathways contribute to the pathophysiology of mood disorders, based on the premise that fluctuations in sex hormones influence mood, a relationship particularly evident in conditions such as premenstrual dysphoric disorder, prenatal depression, postpartum depression, and perimenopausal depression. Estrogen receptor alpha (ER) is predominantly localized in the nucleus, but can also be associated with the cell membrane, thus mediating a broad range of genomic and non-genomic effects through distinct intracellular pathways. By employing a combination of computational simulations and in vitro biochemical and cell-based assays, we systematically evaluated the potential binding and functional interactions of antidepressant compounds with ER. Our results provide compelling evidence that antidepressants may not only affect classical monoaminergic targets but also modulate hormone receptor activity, particularly that of ER. These findings are consistent with the hypothesis that ER plays an important role in mood regulation and highlight it as a potential therapeutic target. Moreover, this work raises the possibility that the clinical efficacy of certain antidepressants may, at least in part, derive from their capacity to influence estrogen receptor-mediated signaling. Significance statementClinical observations suggest a link between female sex hormones and mood, highlighted by the higher prevalence of depression in women and increased vulnerability to depression during hormonal fluctuations. Here, we report that structurally diverse conventional and rapid-acting antidepressants directly interact with estrogen receptor alpha (ER). This interaction is associated with rapid intracellular signaling in cellular models. These findings indicate that, alongside their conventional targets, antidepressants may also engage sex steroid receptor components and signaling. This work broadens our basic understanding of antidepressant pharmacology at the cellular level, offering an additional perspective that may inform future research into the biological mechanisms of mood disorders and suggest a framework for developing targeted therapies for hormone-associated depressive disorders.

pharmacology and toxicology↗

bioRxiv2025

Extracellular vesicles from morphine-exposed prefrontal cortex carry transcriptomic and proteomic signatures of synaptic dysfunction

Extracellular vesicles (EVs) released by neurons and glial cells mediate intercellular communication in the brain and regulate synaptic function, neuronal survival, and neuropathological processes. Although chronic opioid exposure induces widespread neuroadaptations, the contribution of brain-derived EVs (BDEVs) to these processes remains largely unknown. Here, we isolated BDEVs from the prefrontal cortex of rats chronically exposed to morphine and performed integrative transcriptomic and proteomic analyses of their molecular cargo. Total RNA sequencing combined with unbiased proteomics revealed that morphine profoundly reprograms the BDEV transcriptome and proteome, enriching pathways related to synaptic plasticity, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and neurodegeneration. Among the most prominent alterations, the synaptic regulator ARC was consistently modulated at the mRNA level, while the ER stress marker HSPA5 was altered at both mRNA and protein levels. Functional assays further demonstrated that BDEVs derived from morphine-treated rats were sufficient to reconfigure transcriptional programs in naive cortical neurons, affecting genes associated with synaptic remodeling and excitability. Collectively, these findings provide the first evidence that chronic opioid exposure reprograms BDEV cargo in a brain region critical for addiction and that these vesicles can propagate transcriptional reorganization to recipient neurons. BDEVs thus emerge as active mediators of morphine-induced neuroadaptations and as potential targets for biomarker discovery and therapeutic intervention in opioid use disorder.

neuroscience↗

bioRxiv2025

Soluble SORL1 in cerebrospinal fluid as a marker for functional impact of rare SORL1 variants.

BackgroundAs part of the retromer, sortilin-related receptor (SORL1) sorts cargo proteins away from the endosome to the trans-Golgi network or to the cell surface, where SORL1 is cleaved into sSORL1 and shed into the interstitial fluid and CSF. SORL1s cargo includes APP and A{beta}, which may explain why protein-truncating genetic variants (PTVs) in SORL1 are observed almost exclusively in Alzheimers Disease (AD) patients, and that rare, predicted pathogenic missense variants have been associated with a 10-fold increased risk of AD. However, functional evidence supporting variant pathogenicity is warranted. Here we investigated whether soluble SORL1 (sSORL1) concentrations in cerebrospinal fluid (CSF) offer a potential in vivo biomarker to support impaired SORL1 function in variant carriers. MethodsUsing an ELISA assay for SORL1 (ABCAM), we determined sSORL1 concentrations in CSF from 218 participants of the Alzheimer Dementia Cohort (ADC) (54% females). We compared sSORL1 in CSF derived from 90 carriers of diverse SORL1 variants with concentrations observed in 78 SORL1-WT AD patients, and 50 SORL1-WT controls for whom CSF-pTau-181, CSF-tTau, CSF-A{beta}42 concentrations were available. In a subset of 36 individuals, we used Western blotting (WB) to validate sSORL1 concentrations as determined by ELISA. ResultsCSF-sSORL1 concentrations did not differ between SORL1-WT AD patients and controls. While CSF-sSORL1 did not correlate with CSF-A{beta}42 concentrations in SORL1-WT AD patients (p=0.62), it correlated with sCSF-ptau-181 (p=9.7x10-6). The mean CSF-sSORL1 concentration in the SORL1 WT AD cases and controls was 466 pg/ml, with wide variance (SD = 133). Comparatively, concentrations were significantly lower in PTV carriers (260 pg/ml, p=3.2x10-7) and in carriers of predicted damaging SORL1 missense variants (323 pg/ml, p=2.4x10-7). CSF-sSORL1 concentrations measured by ELISA correlated strongly with concentrations estimated by WB ({rho}=0.552; p=5.0x10-4). ConclusionCSF-sSORL1 increases with CSF-ptau, suggesting that increased SORL1-retromer activity may serve to rescue cellular stress associated with AD-related processes. However, impairing SORL1 genetic variants may preclude SORL1 trafficking to the cell surface, as supported by lower CSF-sSORL1 protein concentrations in carriers. While further refinements are necessary, we present first evidence for the applicability of ELISA-based quantification of sSORL1 in CSF to evaluate the functional impact of rare SORL1 variants.

neuroscience↗

bioRxiv2025

Meteorin resolves nociceptive hypersensitivity by reducing connexin-mediated coupling in satellite glial cells

Neuropathic pain, a persistent condition arising from injury to the nervous system, involves complex interactions between neurons and non-neuronal cells, including satellite glial cells (SGCs) in the dorsal root ganglia (DRG). In this study, we examined the glial-targeting effects of meteorin, a neurotrophic protein with gliogenic properties, using mouse models of neuropathic and inflammatory pain. Systemic meteorin administration reversed mechanical hypersensitivity across diverse neuropathic and inflammatory pain models, with therapeutic effects persisting beyond the treatment period. We identified SGCs as the principal site of meteorin expression and action in the DRG, where it selectively activated SGCs and altered their functional state. Proteomic profiling revealed meteorin-mediated downregulation of gap junction proteins in SGCs, particularly connexin 43, which was corroborated by immunohistochemical analyses. Functional assessments demonstrated that meteorin treatment normalized injury-induced increases in intercellular coupling between SGCs, establishing a mechanistic link between glial network modulation and pain resolution. These findings identify meteorin as a regulator of SGC communication through connexin-dependent mechanisms. The sustained therapeutic effects and multi-model efficacy highlight meteorin as a potential intervention for neuropathic pain while advancing our understanding of SGC plasticity in sensory processing.

neuroscience↗

bioRxiv2025

Mapping satellite glial cell heterogeneity reveals distinct spatial organization and signifies functional diversity in the dorsal root ganglion

Satellite glial cells (SGCs) envelop the somata, axon hillock, and initial axon segment of sensory neurons in the dorsal root ganglia (DRG), playing a critical role in regulating the neuronal microenvironment. While DRG neurons have been extensively studied and classified based on size, molecular markers, and functional characteristics, very little is still known about SGC heterogeneity and its potential implications on sensory processing in the DRG. Single cell transcriptional analyses have proposed the existence of SGC subtypes, yet in situ validation, spatial distribution, and potential functional implications of such subtypes are still largely unexplored. Here, we present the first comprehensive in situ characterization of SGC heterogeneity within the mouse DRG. By integrating single-cell RNA sequencing with immunohistochemistry, in situ hybridization, and advanced imaging techniques, distinct SGC subclusters were identified, validated, and spatially mapped within their native anatomical context. We visually identify four distinct subpopulations: 1) a predominant population of perisomatic SGC sheaths defined by the expression of marker proteins traditionally used to characterize the entire SGC population, including FABP7, KIR4.1, GS, and CX43. 2) OCT6+ SGCs occasionally being found in mosaic perisomatic sheaths, and consistently associated with axonal glomeruli, primarily ensheathing initial segment axon. 3) SCN7A+ SGCs, exhibiting no/low expression of traditional SGC markers and forming specialized homogenous sheaths around non-peptidergic neuron subtypes, implicating their potential role in pruritic (itch-related) conditions. 4) Interferon response gene-expressing SGCs, responding to Herpes Simplex Virus infection, suggesting potential involvement in antiviral protection. Finally, we investigate human DRG and find an inner perisomatic SGC layer surrounded by an outer SGC layer, with traditional and novel markers distinctively distributed between the two layers. Our results provide novel insight into SGC heterogeneity in the DRG and suggests distinct functional properties for such subtypes of relevance for the neuronal microenvironment.

neuroscience↗

bioRxiv2024

Electromagnetic Stimulated Microfillamented Hydrogels for Guided Neuronal Morphogenesis

Biohybrid materials that integrate structural and bioelectronic cues across scales offer new routes to regulate neural development and repair. We present a hybrid, hydrogel-electromagnetic stimulation platform with a 3D hierarchically anisotropic structure, combining FLight bioprinted hydrogel microfilaments with a melt-electrowritten wireless electromagnetic stimulation system, to guide neural morphogenesis across central and peripheral systems at cellular and tissue scale. In the central nervous system, the soft microfilaments selectively promoted healthy, white-matter-like neurite extension rather than glioblastoma-derived outgrowth in human cortical brain tissues, while the electrically stimulation further enhanced the hippocampal neurosphere networking along the microfilaments. As a peripheral nerve conduit, the system directs dorsal root ganglion alignment in vitro and, in rat sciatic defects, drives a coordinated pro-regenerative response that improves axonal guidance, remyelination, and functional recovery. This multiscale biohybrid strategy demonstrates how synergistic integration of soft biomaterials and systematic, wireless bioelectric cues can non-invasively regulate neural morphogenesis, establishing new design principles for next-generation bioelectronic interfaces and regenerative medicine.

bioengineering↗

bioRxiv2024

Bradykinesia and postural instability in a model of prodromal Synucleinopathy with alpha-Synuclein aggregation in the gigantocellular nuclei.

-Synuclein (aSyn) accumulation within the extra-nigral neuronal populations in brainstem, including the gigantocellular nuclei (GRN/Gi) of reticular formation, is a recognized feature during the prodromal phase of Parkinson disease (PD). Accordingly, there is a burgeoning interest in animal model development for understanding the pathological significance of extra-nigral synucleinopathy, in relation to motor and/or non-motor symptomatology in PD. Here, we report an experimental paradigm for the induction of aSyn aggregation in brainstem, with stereotaxic delivery of pre-formed fibrillar (PFF) aSyn in the pontine GRN of transgenic mice expressing the mutant human Ala53Thr aSyn (M83 line). Our data show that PFF aSyn-induced aggregate pathology in GRN leads to progressive decline in spontaneous locomotion and an early phenotype of postural instability. This early phase of bradykinesia was followed by a moribund stage, characterized by worsening motor performance and impaired survival with substantial aSyn aggregation in several brain regions beyond the GRN. Collectively, our observations suggest an experimental framework for studying the pathological significance of aSyn aggregation in GRN in relation to features of movement disability in PD. With further refinements, we anticipate that this model holds promise as a test-bed for translational research in PD and related disorders.

neuroscience↗

bioRxiv2023

Recombinant dimeric PDZ protein inhibitors for long-term relief of chronic pain by AAV therapeutics

The inadequate state of current pain treatments, the chronic nature of particularly neuropathic pain, and the high impact on quality of life render chronic pain conditions relevant for gene therapy. Here, we describe the development and application of self-assembling dimeric peptide inhibitors of the pain-associated scaffolding protein PICK1 (protein interacting with C-kinase 1) delivered by adeno-associated viral (AAV) vectors. In mice, these peptides prevented mechanical allodynia in inflammatory and neuropathic pain models and reversed neuropathic pain in advanced stages up to one year. Pain relief was obtained by targeting several relays along the somatosensory pain pathways unaccompanied by overt adverse side effects, while selective transduction of peripheral neurons was sufficient for providing full pain relief. We further confirmed PICK1 expression and peptide target engagement in mice and human donor tissue, and we conclude that AAV therapeutics, based on recombinant PICK1 inhibitors, represent a potential clinically meaningful strategy for persistent neuropathic pain conditions. One Sentence SummaryAlleviating neuropathic pain by PICK1-directed gene therapy.

neuroscience↗

bioRxiv2021

Comparative transcriptional analysis of the satellite glial cell injury response

Satellite glial cells (SGCs) tightly surround and support primary sensory neurons in the peripheral nervous system and are increasingly recognized for their involvement in the development of neuropathic pain following nerve injury. The SGCs are difficult to investigate due to their flattened shape and tight physical connection to neurons in vivo and their rapid changes in phenotype and protein expression when cultured in vitro. Consequently, several aspects of SGC function under normal conditions as well as after a nerve injury remain to be explored. The recent advance in single cell RNAseq technologies has enabled a new approach to investigate SGCs. Here we publish a dataset from mice subjected to sciatic nerve injury as well as a dataset from dorsal root ganglia cells after 3 days in culture. We use a meta-analysis approach to compare the injury response with that in other published datasets and conclude that SGCs share a common signature following sciatic nerve crush and sciatic ligation, involving transcriptional regulation of cholesterol biosynthesis. We also observed a considerable transcriptional change when culturing SGCs, suggesting that some differentiate into a specialised in vitro state, while others start resembling Schwann cell-like precursors. The datasets are available via the Broad Institute Single Cell Portal.

neuroscience↗

bioRxiv2021

α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response

Circumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleionpathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2) is recognized as the master regulator of cellular anti-oxidant response, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, Prnp-SNCA*Ala53Thr), which manifest widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.

neuroscience↗

bioRxiv2020

SorCS1 binds the insulin receptor to enhance insulin sensitivity

Type 2 diabetes has reached endemic proportions and is a substantial burden for the affected patients and the society. Along with lifestyle factors, a number of genetic loci predisposing to type 2 diabetes have been identified, including SORCS1 that encodes the transmembrane receptor SorCS1. The ectodomain of SorCS1 (sol-SorCS1) is shed from plasma membranes but the biological function of this fragment is unknown. Here we show that sol-SorCS1 acts as a high-affinity binding partner for the insulin receptor to stabilize the receptor and increase insulin affinity, protein kinase B activation, and glucose uptake in myocytes. Sol-SorCS1 is liberated from adipocytes, and in diabetic patients the plasma concentration positively correlates with body mass index, but inversely with plasma glucose. In mouse models of insulin resistance, exogenous sol-SorCS1 restored insulin sensitivity. We conclude that sol-SorCS1 increases peripheral insulin sensitivity and propose sol-SorCS1 as a novel insulin sensitizing adipokine and potential antidiabetic agent.

physiology↗

bioRxiv2020

Endosomal trafficking is required for glycosylation and normal maturation of the Alzheimer's-associated protein sorLA

The sorting receptor sorLA encoded by the SORL1 gene is implicated in Alzheimers disease (AD) pathogenesis. Genetic studies have identified AD-associated SORL1 mutations and the expression of sorLA in AD brains is reported to be reduced. SorLA is a receptor of the retromer trafficking complex and functions at the endosome, and deficiency in sorLA phenocopies the endosomal pathologies found in AD. SorLA undergoes posttranslational modifications and maturation with ultimate ectodomain shedding, however knowledge of these processes remains limited. Here we demonstrate that sorLA exists at the cell membrane in two forms, an immature and a mature form, characterized by distinct N-glycosylation profiles. The mature sorLA form has acquired complex type N-glycans and is shed from the cell surface by the TACE juxtmembrane cleavage. The immature form of sorLA present at the cell surface is shown to have immature ER-type N-glycans (high-mannose type susceptible to endo H) and does not undergo shedding, however, upon endocytosis and recycling to the cell surface via endosomal trafficking pathways the immature sorLA form acquires complex-type N-glycans. These results suggest an unusual secretion model for sorLA whereby that immature sorLA first traffics to the cell membrane without acquiring Golgi processing of N-glycans, and only upon retrograde trafficking does sorLA acquire normal Golgi maturation of N-glycans and become susceptible to TACE regulated shedding. Supportive evidence for this model include a sorLA mutant with deficient endosomal trafficking and in vivo studies demonstrating requirement of retromer for sorLA trafficking in the brain of retromer VPS26 deficient mice. Collectively, our study establishes the role endosomal trafficking plays in sorLAs normal maturation, and point to impaired maturation as a signature of AD-associated sorLA dysfunction.

cell biology↗