121 results on '"Willnow TE"'
Search Results
2. Effects of knocking out Vps10p-domain receptor family proteins in anti-NGF transgenic mice
- Author
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CAPSONI, SIMONA, CATTANEO, ANTONINO, AMATO G, VIGNONE D, NYKJAER A, WILLNOW TE, Capsoni, Simona, Amato, G, Vignone, D, Nykjaer, A, Willnow, Te, and Cattaneo, Antonino
- Published
- 2009
3. Megalin is essential for renal proximal tubule reabsorption of iii in-DTPA-octreotide
- Author
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Jong, Marion, Barone, R, Krenning, Eric, Bernard, HF, Melis, M, Visser, Theo, Gekle, M, Willnow, TE, Walrand, S, Jamar, F, Pauwels, S, Radiology & Nuclear Medicine, and Internal Medicine
- Published
- 2005
4. Megalin is essential for renal proximal tubule reabsorption of In-111-DTPA-octreotide
- Author
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Jong, Marion, Barone, R, Krenning, Eric, Bernard, HF, Melis, M, Visser, Theo, Gekle, M, Willnow, TE, Walrand, S, Jamar, F, Pauwels, S, Radiology & Nuclear Medicine, and Internal Medicine
- Published
- 2005
5. SorLA restricts TNFα release from microglia to shape a glioma-supportive brain microenvironment.
- Author
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Kaminska P, Ovesen PL, Jakiel M, Obrebski T, Schmidt V, Draminski M, Bilska AG, Bieniek M, Anink J, Paterczyk B, Jensen AMG, Piatek S, Andersen OM, Aronica E, Willnow TE, Kaminska B, Dabrowski MJ, and Malik AR
- Subjects
- Animals, Humans, Mice, Brain metabolism, Brain pathology, Cell Line, Tumor, Disease Models, Animal, Glioblastoma metabolism, Glioblastoma pathology, Glioblastoma genetics, Macrophages metabolism, Brain Neoplasms metabolism, Brain Neoplasms pathology, Brain Neoplasms genetics, Glioma metabolism, Glioma pathology, Glioma genetics, Membrane Transport Proteins metabolism, Membrane Transport Proteins genetics, Microglia metabolism, Microglia pathology, Tumor Microenvironment, Tumor Necrosis Factor-alpha metabolism, LDL-Receptor Related Proteins genetics, LDL-Receptor Related Proteins metabolism
- Abstract
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., (© 2024. The Author(s).)
- Published
- 2024
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6. Elevated sortilin expression discriminates functional from non-functional neuroendocrine tumors and enables therapeutic targeting.
- Author
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Bolduan F, Wetzel A, Giesecke Y, Eichhorn I, Alenina N, Bader M, Willnow TE, Wiedenmann B, and Sigal M
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- Female, Humans, Male, Biomarkers, Tumor metabolism, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Malignant Carcinoid Syndrome metabolism, Middle Aged, Animals, Mice, Adaptor Proteins, Vesicular Transport metabolism, Neuroendocrine Tumors metabolism, Neuroendocrine Tumors pathology, Serotonin metabolism
- Abstract
A subset of neuroendocrine tumors (NETs) can cause an excessive secretion of hormones, neuropeptides, and biogenic amines into the bloodstream. These so-called functional NETs evoke a hormone-related disease and lead to several different syndromes, depending on the factors released. One of the most common functional syndromes, carcinoid syndrome, is characterized mainly by over-secretion of serotonin. However, what distinguishes functional from non-functional tumors on a molecular level remains unknown. Here, we demonstrate that the expression of sortilin, a widely expressed transmembrane receptor involved in intracellular protein sorting, is significantly increased in functional compared to non-functional NETs and thus can be used as a biomarker for functional NETs. Furthermore, using a cell line model of functional NETs, as well as organoids, we demonstrate that inhibition of sortilin reduces cellular serotonin concentrations and may therefore serve as a novel therapeutic target to treat patients with carcinoid syndrome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bolduan, Wetzel, Giesecke, Eichhorn, Alenina, Bader, Willnow, Wiedenmann and Sigal.)
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- 2024
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7. Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment.
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Juul-Madsen K, Parbo P, Ismail R, Ovesen PL, Schmidt V, Madsen LS, Thyrsted J, Gierl S, Breum M, Larsen A, Andersen MN, Romero-Ramos M, Holm CK, Andersen GR, Zhao H, Schuck P, Nygaard JV, Sutherland DS, Eskildsen SF, Willnow TE, Brooks DJ, and Vorup-Jensen T
- Subjects
- Humans, Integrin alphaXbeta2, Monocytes pathology, Alzheimer Disease pathology, Amyloid beta-Peptides, Cognitive Dysfunction
- Abstract
The peripheral immune system is important in neurodegenerative diseases, both in protecting and inflaming the brain, but the underlying mechanisms remain elusive. Alzheimer's Disease is commonly preceded by a prodromal period. Here, we report the presence of large Aβ aggregates in plasma from patients with mild cognitive impairment (n = 38). The aggregates are associated with low level Alzheimer's Disease-like brain pathology as observed by
11 C-PiB PET and18 F-FTP PET and lowered CD18-rich monocytes. We characterize complement receptor 4 as a strong binder of amyloids and show Aβ aggregates are preferentially phagocytosed and stimulate lysosomal activity through this receptor in stem cell-derived microglia. KIM127 integrin activation in monocytes promotes size selective phagocytosis of Aβ. Hydrodynamic calculations suggest Aβ aggregates associate with vessel walls of the cortical capillaries. In turn, we hypothesize aggregates may provide an adhesion substrate for recruiting CD18-rich monocytes into the cortex. Our results support a role for complement receptor 4 in regulating amyloid homeostasis., (© 2024. The Author(s).)- Published
- 2024
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8. SORCS2 activity in pancreatic α-cells safeguards insulin granule formation and release from glucose-stressed β-cells.
- Author
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Kalnytska O, Qvist P, Kunz S, Conrad T, Willnow TE, and Schmidt V
- Abstract
Sorting receptor SORCS2 is a stress-response factor protecting neurons from acute insults, such as during epilepsy. SORCS2 is also expressed in the pancreas, yet its action in this tissue remains unknown. Combining metabolic studies in SORCS2-deficient mice with ex vivo functional analyses and single-cell transcriptomics of pancreatic tissues, we identified a role for SORCS2 in protective stress response in pancreatic islets, essential to sustain insulin release. We show that SORCS2 is predominantly expressed in islet alpha cells. Loss of expression coincides with inability of these cells to produce osteopontin, a secreted factor that facilitates insulin release from stressed beta cells. In line with diminished osteopontin levels, beta cells in SORCS2-deficient islets show gene expression patterns indicative of aggravated cell stress, and exhibit defects in insulin granule maturation and a blunted glucose response. These findings corroborate a function for SORCS2 in protective stress response that extends to metabolism., Competing Interests: The authors declare no competing interest related to this manuscript., (© 2023 The Author(s).)
- Published
- 2023
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9. Spatially and temporally distinct patterns of expression for VPS10P domain receptors in human cerebral organoids.
- Author
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Febbraro F, Andersen HHB, Kitt MM, and Willnow TE
- Abstract
Vacuolar protein sorting 10 protein (VPS10P) domain receptors are a unique class of intracellular sorting receptors that emerge as major risk factors associated with psychiatric and neurodegenerative diseases, including bipolar disorders, autism, schizophrenia, as well as Alzheimer's disease and frontotemporal dementia. Yet, the lack of suitable experimental models to study receptor functions in the human brain has hampered elucidation of receptor actions in brain disease. Here, we have adapted protocols using human cerebral organoids to the detailed characterization of VPS10P domain receptor expression during neural development and differentiation, including single-cell RNA sequencing. Our studies uncovered spatial and temporal patterns of expression unique to individual receptor species in the human brain. While SORL1 expression is abundant in stem cells and SORCS1 peaks in neural progenitors at onset of neurogenesis, SORT1 and SORCS2 show increasing expression with maturation of neuronal and non-neuronal cell types, arguing for distinct functions in development versus the adult brain. In neurons, subcellular localization also distinguishes between types of receptor species, either mainly localized to the cell soma ( SORL1 and SORT1 ) or also to neuronal projections ( SORCS1 and SORCS2 ), suggesting divergent functions in protein sorting between Golgi and the endo-lysosomal system or along axonal and dendritic tracks. Taken together, our findings provide an important resource on temporal, spatial, and subcellular patterns of VPS10P domain receptor expression in cerebral organoids for further elucidation of receptor (dys) functions causative of behavioral and cognitive defects of the human brain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Febbraro, Andersen, Kitt and Willnow.)
- Published
- 2023
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10. Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames.
- Author
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Sandmann CL, Schulz JF, Ruiz-Orera J, Kirchner M, Ziehm M, Adami E, Marczenke M, Christ A, Liebe N, Greiner J, Schoenenberger A, Muecke MB, Liang N, Moritz RL, Sun Z, Deutsch EW, Gotthardt M, Mudge JM, Prensner JR, Willnow TE, Mertins P, van Heesch S, and Hubner N
- Subjects
- Humans, Open Reading Frames, Proteomics, Micropeptides, Peptides genetics, Protein Biosynthesis
- Abstract
All species continuously evolve short open reading frames (sORFs) that can be templated for protein synthesis and may provide raw materials for evolutionary adaptation. We analyzed the evolutionary origins of 7,264 recently cataloged human sORFs and found that most were evolutionarily young and had emerged de novo. We additionally identified 221 previously missed sORFs potentially translated into peptides of up to 15 amino acids-all of which are smaller than the smallest human microprotein annotated to date. To investigate the bioactivity of sORF-encoded small peptides and young microproteins, we subjected 266 candidates to a mass-spectrometry-based interactome screen with motif resolution. Based on these interactomes and additional cellular assays, we can associate several candidates with mRNA splicing, translational regulation, and endocytosis. Our work provides insights into the evolutionary origins and interaction potential of young and small proteins, thereby helping to elucidate this underexplored territory of the human proteome., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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11. Regulation of Prostate Androgens by Megalin and 25-hydroxyvitamin D Status: Mechanism for High Prostate Androgens in African American Men.
- Author
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Garcia J, Krieger KD, Loitz C, Perez LM, Richards ZA, Helou Y, Kregel S, Celada S, Mesaros CA, Bosland M, Gann PH, Willnow TE, Vander Griend D, Kittles R, Prins GS, Penning T, and Nonn L
- Subjects
- Animals, Humans, Male, Mice, Black or African American, Prostate metabolism, Testosterone, Vitamin D metabolism, Androgens, Calcifediol, Low Density Lipoprotein Receptor-Related Protein-2 metabolism, Prostatic Neoplasms, Vitamin D Deficiency
- Abstract
Vitamin D deficiency is associated with an increased risk of prostate cancer mortality and is hypothesized to contribute to prostate cancer aggressiveness and disparities in African American populations. The prostate epithelium was recently shown to express megalin, an endocytic receptor that internalizes circulating globulin-bound hormones, which suggests regulation of intracellular prostate hormone levels. This contrasts with passive diffusion of hormones that is posited by the free hormone hypothesis. Here, we demonstrate that megalin imports testosterone bound to sex hormone-binding globulin into prostate cells. Prostatic loss of Lrp2 (megalin) in a mouse model resulted in reduced prostate testosterone and dihydrotestosterone levels. Megalin expression was regulated and suppressed by 25-hydroxyvitamin D (25D) in cell lines, patient-derived prostate epithelial cells, and prostate tissue explants. In patients, the relationships between hormones support this regulatory mechanism, as prostatic DHT levels are higher in African American men and are inversely correlated with serum 25D status. Megalin levels are reduced in localized prostate cancer by Gleason grade. Our findings suggest that the free hormone hypothesis should be revisited for testosterone and highlight the impact of vitamin D deficiency on prostate androgen levels, which is a known driver of prostate cancer. Thus, we revealed a mechanistic link between vitamin D and prostate cancer disparities observed in African Americans., Significance: These findings link vitamin D deficiency and the megalin protein to increased levels of prostate androgens, which may underpin the disparity in lethal prostate cancer in African America men., (© 2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
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12. SORLA mediates endocytic uptake of proIAPP and protects against islet amyloid deposition.
- Author
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Shih AZL, Chen YC, Speckmann T, Søndergaard E, Schürmann A, Verchere CB, and Willnow TE
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- Amyloid genetics, Amyloid metabolism, Animals, Humans, Islet Amyloid Polypeptide genetics, Islet Amyloid Polypeptide metabolism, Membrane Transport Proteins deficiency, Membrane Transport Proteins genetics, Mice, Mice, Transgenic, Receptors, LDL deficiency, Receptors, LDL genetics, Amyloidosis metabolism, Amyloidosis pathology, Insulin-Secreting Cells metabolism, Islets of Langerhans metabolism
- Abstract
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., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2022
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13. SORLA is required for insulin-induced expansion of the adipocyte precursor pool in visceral fat.
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Schmidt V, Horváth C, Dong H, Blüher M, Qvist P, Wolfrum C, and Willnow TE
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- Adipocytes drug effects, Adipocytes metabolism, Adipose Tissue, White drug effects, Adipose Tissue, White metabolism, Adult, Aged, Aged, 80 and over, Animals, Body Mass Index, Cell Proliferation drug effects, Female, Humans, Male, Mice, Inbred C57BL, Middle Aged, Mitogens pharmacology, Stem Cells drug effects, Subcutaneous Fat drug effects, Subcutaneous Fat metabolism, Young Adult, Mice, Adipocytes cytology, Insulin pharmacology, Intra-Abdominal Fat metabolism, LDL-Receptor Related Proteins metabolism, Membrane Transport Proteins metabolism, Receptors, LDL metabolism, Stem Cells cytology, Stem Cells metabolism
- Abstract
Visceral adipose tissue shows remarkable plasticity, constantly replacing mature adipocytes from an inherent pool of adipocyte precursors. The number of precursors is set in the juvenile organism and remains constant in adult life. Which signals drive precursor pool expansion in juveniles and why they operate in visceral but not in subcutaneous white adipose tissue (WAT) are unclear. Using mouse models, we identified the insulin-sensitizing receptor SORLA as a molecular factor explaining the distinct proliferative capacity of visceral WAT. High levels of SORLA activity in precursors of juvenile visceral WAT prime these cells for nutritional stimuli provided through insulin, promoting mitotic expansion of the visceral precursor cell pool in overfed juvenile mice. SORLA activity is low in subcutaneous precursors, blunting their response to insulin and preventing diet-induced proliferation of this cell type. Our findings provide a molecular explanation for the unique proliferative properties of juvenile visceral WAT, and for the genetic association of SORLA with visceral obesity in humans., (© 2021 Schmidt et al.)
- Published
- 2021
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14. GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium.
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Marczenke M, Sunaga-Franze DY, Popp O, Althaus IW, Sauer S, Mertins P, Christ A, Allen BL, and Willnow TE
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- Animals, Cell Cycle Proteins deficiency, Cell Differentiation, Embryo, Mammalian, Epithelial Cells cytology, Epithelial Cells metabolism, Epithelium metabolism, GPI-Linked Proteins deficiency, GPI-Linked Proteins metabolism, Humans, Mice, Mutation, Neural Stem Cells cytology, Neural Stem Cells metabolism, Patched-1 Receptor metabolism, Pluripotent Stem Cells cytology, Pluripotent Stem Cells metabolism, Prosencephalon cytology, Prosencephalon embryology, Signal Transduction, Cell Cycle Proteins metabolism, Hedgehog Proteins metabolism, Prosencephalon metabolism, Receptor, Notch1 metabolism
- Abstract
Growth arrest-specific 1 (GAS1) acts as a co-receptor to patched 1, promoting sonic hedgehog (SHH) signaling in the developing nervous system. GAS1 mutations in humans and animal models result in forebrain and craniofacial malformations, defects ascribed to a function for GAS1 in SHH signaling during early neurulation. Here, we confirm loss of SHH activity in the forebrain neuroepithelium in GAS1-deficient mice and in induced pluripotent stem cell-derived cell models of human neuroepithelial differentiation. However, our studies document that this defect can be attributed, at least in part, to a novel role for GAS1 in facilitating NOTCH signaling, which is essential to sustain a persistent SHH activity domain in the forebrain neuroepithelium. GAS1 directly binds NOTCH1, enhancing ligand-induced processing of the NOTCH1 intracellular domain, which drives NOTCH pathway activity in the developing forebrain. Our findings identify a unique role for GAS1 in integrating NOTCH and SHH signal reception in neuroepithelial cells, and they suggest that loss of GAS1-dependent NOTCH1 activation contributes to forebrain malformations in individuals carrying GAS1 mutations., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)
- Published
- 2021
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15. ApoE4 disrupts interaction of sortilin with fatty acid-binding protein 7 essential to promote lipid signaling.
- Author
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Asaro A, Sinha R, Bakun M, Kalnytska O, Carlo-Spiewok AS, Rubel T, Rozeboom A, Dadlez M, Kaminska B, Aronica E, Malik AR, and Willnow TE
- Subjects
- Adaptor Proteins, Vesicular Transport, Animals, Apolipoprotein E3, Fatty Acid-Binding Protein 7, Humans, Lipids, Mice, Alzheimer Disease genetics, Apolipoprotein E4 genetics, Apolipoprotein E4 metabolism
- Abstract
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., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)
- Published
- 2021
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16. Corrigendum to Flemming J, Marczenke M, Rudolph I-M, et al. Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome. Kidney Int. 2020;98:159-167.
- Author
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Flemming J, Marczenke M, Rudolph IM, Nielsen R, Storm T, Ilsoe Christensen E, Diecke S, Emma F, and Willnow TE
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- 2021
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17. Is LRP2 Involved in Leptin Transport over the Blood-Brain Barrier and Development of Obesity?
- Author
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Sandin ES, Folberth J, Müller-Fielitz H, Pietrzik CU, Herold E, Willnow TE, Pfluger PT, Nogueiras R, Prevot V, Krey T, and Schwaninger M
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- Animals, Binding Sites, Body Composition, Body Weight, CHO Cells, Choroid Plexus metabolism, Cricetulus, Endothelial Cells metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Female, Luciferases metabolism, Male, Models, Biological, Phosphorylation, Protein Transport, Receptors, Leptin metabolism, Recombinant Fusion Proteins metabolism, Swine, Blood-Brain Barrier metabolism, Leptin metabolism, Low Density Lipoprotein Receptor-Related Protein-2 metabolism, Obesity metabolism, Obesity pathology
- Abstract
The mechanisms underlying the transport of leptin into the brain are still largely unclear. While the leptin receptor has been implicated in the transport process, recent evidence has suggested an additional role of LRP2 (megalin). To evaluate the function of LRP2 for leptin transport across the blood-brain barrier (BBB), we developed a novel leptin-luciferase fusion protein (pLG), which stimulated leptin signaling and was transported in an in vitro BBB model based on porcine endothelial cells. The LRP inhibitor RAP did not affect leptin transport, arguing against a role of LRP2. In line with this, the selective deletion of LRP2 in brain endothelial cells and epithelial cells of the choroid plexus did not influence bodyweight, body composition, food intake, or energy expenditure of mice. These findings suggest that LRP2 at the BBB is not involved in the transport of leptin into the brain, nor in the development of obesity as has previously been described.
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- 2021
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18. LRP2 controls sonic hedgehog-dependent differentiation of cardiac progenitor cells during outflow tract formation.
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Christ A, Marczenke M, and Willnow TE
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- Animals, Cell Lineage, Cell Movement, Cell Proliferation, Female, Heart Defects, Congenital etiology, Heart Defects, Congenital metabolism, Hedgehog Proteins genetics, Mice, Mice, Knockout, Myocytes, Cardiac metabolism, Signal Transduction, Stem Cells metabolism, Cell Differentiation, Heart Defects, Congenital pathology, Hedgehog Proteins metabolism, Low Density Lipoprotein Receptor-Related Protein-2 physiology, Morphogenesis, Myocytes, Cardiac pathology, Stem Cells pathology
- Abstract
Conotruncal malformations are a major cause of congenital heart defects in newborn infants. Recently, genetic screens in humans and in mouse models have identified mutations in LRP2, a multi-ligand receptor, as a novel cause of a common arterial trunk, a severe form of outflow tract (OFT) defect. Yet, the underlying mechanism why the morphogen receptor LRP2 is essential for OFT development remained unexplained. Studying LRP2-deficient mouse models, we now show that LRP2 is expressed in the cardiac progenitor niche of the anterior second heart field (SHF) that contributes to the elongation of the OFT during separation into aorta and pulmonary trunk. Loss of LRP2 in mutant mice results in the depletion of a pool of sonic hedgehog-dependent progenitor cells in the anterior SHF due to premature differentiation into cardiomyocytes as they migrate into the OFT myocardium. Depletion of this cardiac progenitor cell pool results in aberrant shortening of the OFT, the likely cause of CAT formation in affected mice. Our findings identified the molecular mechanism whereby LRP2 controls the maintenance of progenitor cell fate in the anterior SHF essential for OFT separation, and why receptor dysfunction is a novel cause of conotruncal malformation., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
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19. Cdon mutation and fetal alcohol converge on Nodal signaling in a mouse model of holoprosencephaly.
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Hong M, Christ A, Christa A, Willnow TE, and Krauss RS
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- Animals, Disease Models, Animal, Female, Maternal Exposure, Mice, Signal Transduction drug effects, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Ethanol adverse effects, Holoprosencephaly chemically induced, Holoprosencephaly genetics, Holoprosencephaly pathology, Mutation genetics, Nodal Protein genetics, Nodal Protein metabolism
- Abstract
Holoprosencephaly (HPE), a defect in midline patterning of the forebrain and midface, arises ~1 in 250 conceptions. It is associated with predisposing mutations in the Nodal and Hedgehog (HH) pathways, with penetrance and expressivity graded by genetic and environmental modifiers, via poorly understood mechanisms. CDON is a multifunctional co-receptor, including for the HH pathway. In mice, Cdon mutation synergizes with fetal alcohol exposure, producing HPE phenotypes closely resembling those seen in humans. We report here that, unexpectedly, Nodal signaling is a major point of synergistic interaction between Cdon mutation and fetal alcohol. Window-of-sensitivity, genetic, and in vitro findings are consistent with a model whereby brief exposure of Cdon mutant embryos to ethanol during gastrulation transiently and partially inhibits Nodal pathway activity, with consequent effects on midline patterning. These results illuminate mechanisms of gene-environment interaction in a multifactorial model of a common birth defect., Competing Interests: MH, AC, AC, TW, RK No competing interests declared, (© 2020, Hong et al.)
- Published
- 2020
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20. Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome.
- Author
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Flemming J, Marczenke M, Rudolph IM, Nielsen R, Storm T, Erik IC, Diecke S, Emma F, and Willnow TE
- Subjects
- Agenesis of Corpus Callosum, Endocytosis, Hearing Loss, Sensorineural, Hernias, Diaphragmatic, Congenital, Humans, Kidney Tubules, Proximal, Ligands, Myopia, Proteinuria, Renal Tubular Transport, Inborn Errors, Induced Pluripotent Stem Cells, Low Density Lipoprotein Receptor-Related Protein-2 genetics
- Abstract
Donnai-Barrow syndrome (DBS) is an autosomal-recessive disorder characterized by multiple pathologies including malformation of forebrain and eyes, as well as resorption defects of the kidney proximal tubule. The underlying cause of DBS are mutations in LRP2, encoding the multifunctional endocytic receptor megalin. Here, we identified a unique missense mutation R3192Q of LRP2 in an affected family that may provide novel insights into the molecular causes of receptor dysfunction in the kidney proximal tubule and other tissues affected in DBS. Using patient-derived induced pluripotent stem cell lines we generated neuroepithelial and kidney cell types as models of the disease. Using these cell models, we documented the inability of megalin R3192Q to properly discharge ligand and ligand-induced receptor decay in lysosomes. Thus, mutant receptors are aberrantly targeted to lysosomes for catabolism, essentially depleting megalin in the presence of ligand in this affected family., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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21. Author Correction: Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity.
- Author
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Seo JA, Kang MC, Yang WM, Hwang WM, Kim SS, Hong SH, Heo JI, Vijyakumar A, de Moura LP, Uner A, Huang H, Lee SH, Lima IS, Park KS, Kim MS, Dagon Y, Willnow TE, Aroda V, Ciaraldi TP, Henry RR, and Kim YB
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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22. Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity.
- Author
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Seo JA, Kang MC, Yang WM, Hwang WM, Kim SS, Hong SH, Heo JI, Vijyakumar A, Pereira de Moura L, Uner A, Huang H, Lee SH, Lima IS, Park KS, Kim MS, Dagon Y, Willnow TE, Aroda V, Ciaraldi TP, Henry RR, and Kim YB
- Subjects
- Adult, Animals, Cell Line, Clusterin blood, Clusterin genetics, Disease Models, Animal, Female, Glucose Clamp Technique, Humans, Hypoglycemic Agents pharmacology, Hypoglycemic Agents therapeutic use, Insulin metabolism, Liver metabolism, Low Density Lipoprotein Receptor-Related Protein-2 genetics, Low Density Lipoprotein Receptor-Related Protein-2 metabolism, Male, Mice, Mice, Knockout, Pioglitazone pharmacology, Pioglitazone therapeutic use, Polycystic Ovary Syndrome blood, Polycystic Ovary Syndrome drug therapy, Receptor, Insulin metabolism, Signal Transduction drug effects, Clusterin metabolism, Glucose metabolism, Insulin Resistance, Muscle, Skeletal metabolism, Polycystic Ovary Syndrome metabolism
- Abstract
Crosstalk between liver and skeletal muscle is vital for glucose homeostasis. Hepatokines, liver-derived proteins that play an important role in regulating muscle metabolism, are important to this communication. Here we identify apolipoprotein J (ApoJ) as a novel hepatokine targeting muscle glucose metabolism and insulin sensitivity through a low-density lipoprotein receptor-related protein-2 (LRP2)-dependent mechanism, coupled with the insulin receptor (IR) signaling cascade. In muscle, LRP2 is necessary for insulin-dependent IR internalization, an initial trigger for insulin signaling, that is crucial in regulating downstream signaling and glucose uptake. Of physiologic significance, deletion of hepatic ApoJ or muscle LRP2 causes insulin resistance and glucose intolerance. In patients with polycystic ovary syndrome and insulin resistance, pioglitazone-induced improvement of insulin action is associated with an increase in muscle ApoJ and LRP2 expression. Thus, the ApoJ-LRP2 axis is a novel endocrine circuit that is central to the maintenance of normal glucose homeostasis and insulin sensitivity.
- Published
- 2020
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23. Excitatory Amino Acid Transporters in Physiology and Disorders of the Central Nervous System.
- Author
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Malik AR and Willnow TE
- Subjects
- Animals, Biological Transport, Brain Diseases pathology, Central Nervous System pathology, Humans, Neurons metabolism, Neurons pathology, Brain Diseases metabolism, Brain Diseases physiopathology, Central Nervous System metabolism, Central Nervous System physiopathology, Glutamate Plasma Membrane Transport Proteins metabolism, Synaptic Transmission
- Abstract
Excitatory amino acid transporters (EAATs) encompass a class of five transporters with distinct expression in neurons and glia of the central nervous system (CNS). EAATs are mainly recognized for their role in uptake of the amino acid glutamate, the major excitatory neurotransmitter. EAATs-mediated clearance of glutamate released by neurons is vital to maintain proper glutamatergic signalling and to prevent toxic accumulation of this amino acid in the extracellular space. In addition, some EAATs also act as chloride channels or mediate the uptake of cysteine, required to produce the reactive oxygen speciesscavenger glutathione. Given their central role in glutamate homeostasis in the brain, as well as their additional activities, it comes as no surprise that EAAT dysfunctions have been implicated in numerous acute or chronic diseases of the CNS, including ischemic stroke and epilepsy, cerebellar ataxias, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Here we review the studies in cellular and animal models, as well as in humans that highlight the roles of EAATs in the pathogenesis of these devastating disorders. We also discuss the mechanisms regulating EAATs expression and intracellular trafficking and new exciting possibilities to modulate EAATs and to provide neuroprotection in course of pathologies affecting the CNS., Competing Interests: The authors declare no conflict of interest.
- Published
- 2019
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24. Progranulin prevents regulatory NK cell cytotoxicity against antiviral T cells.
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Huang A, Shinde PV, Huang J, Senff T, Xu HC, Margotta C, Häussinger D, Willnow TE, Zhang J, Pandyra AA, Timm J, Weggen S, Lang KS, and Lang PA
- Subjects
- Animals, CD8-Positive T-Lymphocytes, Cyclin T, Cyclin-Dependent Kinase 9 metabolism, Cytotoxicity, Immunologic drug effects, Disease Models, Animal, HEK293 Cells, Humans, Killer Cells, Natural drug effects, Killer Cells, Natural metabolism, Liver immunology, Liver pathology, Lymphocyte Activation drug effects, Lymphocytic Choriomeningitis immunology, Lymphocytic choriomeningitis virus, Macrophages metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Progranulins genetics, Progranulins pharmacology, T-Lymphocytes drug effects, T-Lymphocytes metabolism, Virus Diseases, Antiviral Agents pharmacology, Cytotoxicity, Immunologic immunology, Killer Cells, Natural immunology, Progranulins metabolism, T-Lymphocytes immunology
- Abstract
`NK cell-mediated regulation of antigen-specific T cells can contribute to and exacerbate chronic viral infection, but the protective mechanisms against NK cell-mediated attack on T cell immunity are poorly understood. Here, we show that progranulin (PGRN) can reduce NK cell cytotoxicity through reduction of NK cell expansion, granzyme B transcription, and NK cell-mediated lysis of target cells. Following infection with the lymphocytic choriomeningitis virus (LCMV), PGRN levels increased - a phenomenon dependent on the presence of macrophages and type I IFN signaling. Absence of PGRN in mice (Grn-/-) resulted in enhanced NK cell activity, increased NK cell-mediated killing of antiviral T cells, reduced antiviral T cell immunity, and increased viral burden, culminating in increased liver immunopathology. Depletion of NK cells restored antiviral immunity and alleviated pathology during infection in Grn-/- mice. In turn, PGRN treatment improved antiviral T cell immunity. Taken together, we identified PGRN as a critical factor capable of reducing NK cell-mediated attack of antiviral T cells.
- Published
- 2019
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25. SorCS2 Controls Functional Expression of Amino Acid Transporter EAAT3 and Protects Neurons from Oxidative Stress and Epilepsy-Induced Pathology.
- Author
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Malik AR, Szydlowska K, Nizinska K, Asaro A, van Vliet EA, Popp O, Dittmar G, Fritsche-Guenther R, Kirwan JA, Nykjaer A, Lukasiuk K, Aronica E, and Willnow TE
- Subjects
- Animals, Epilepsy metabolism, Epilepsy pathology, Excitatory Amino Acid Transporter 3 biosynthesis, Excitatory Amino Acid Transporter 3 genetics, Female, Humans, Male, Mice, Nerve Tissue Proteins genetics, Neurons pathology, Receptors, Cell Surface genetics, Epilepsy genetics, Excitatory Amino Acid Transporter 3 metabolism, Glutathione metabolism, Nerve Tissue Proteins metabolism, Neurons metabolism, Oxidative Stress physiology, Receptors, Cell Surface metabolism
- Abstract
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., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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26. Control of hepatic gluconeogenesis by Argonaute2.
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Yan X, Wang Z, Bishop CA, Weitkunat K, Feng X, Tarbier M, Luo J, Friedländer MR, Burkhardt R, Klaus S, Willnow TE, and Poy MN
- Subjects
- AMP-Activated Protein Kinase Kinases, Animals, Argonaute Proteins genetics, Blood Glucose metabolism, Cells, Cultured, Fasting metabolism, Mice, Mice, Inbred C57BL, MicroRNAs genetics, MicroRNAs metabolism, Protein Kinases metabolism, Argonaute Proteins metabolism, Gluconeogenesis, Liver metabolism
- Abstract
Objective: The liver performs a central role in regulating energy homeostasis by increasing glucose output during fasting. Recent studies on Argonaute2 (Ago2), a key RNA-binding protein mediating the microRNA pathway, have illustrated its role in adaptive mechanisms according to changes in metabolic demand. Here we sought to characterize the functional role of Ago2 in the liver in the maintenance of systemic glucose homeostasis., Methods: We first analyzed Ago2 expression in mouse primary hepatocyte cultures after modulating extracellular glucose concentrations and in the presence of activators or inhibitors of glucokinase activity. We then characterized a conditional loss-of-function mouse model of Ago2 in liver for alterations in systemic energy metabolism., Results: Here we show that Ago2 expression in liver is directly correlated to extracellular glucose concentrations and that modulating glucokinase activity is adequate to affect hepatic Ago2 levels. Conditional deletion of Ago2 in liver resulted in decreased fasting glucose levels in addition to reducing hepatic glucose production. Moreover, loss of Ago2 promoted hepatic expression of AMP-activated protein kinase α1 (AMPKα1) by de-repressing its targeting by miR-148a, an abundant microRNA in the liver. Deletion of Ago2 from hyperglycemic, obese, and insulin-resistant Lep
ob/ob mice reduced both random and fasted blood glucose levels and body weight and improved insulin sensitivity., Conclusions: These data illustrate a central role for Ago2 in the adaptive response of the liver to fasting. Ago2 mediates the suppression of AMPKα1 by miR-148a, thereby identifying a regulatory link between non-coding RNAs and a key stress regulator in the hepatocyte., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)- Published
- 2018
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27. Single-Cell Transcriptomics Characterizes Cell Types in the Subventricular Zone and Uncovers Molecular Defects Impairing Adult Neurogenesis.
- Author
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Zywitza V, Misios A, Bunatyan L, Willnow TE, and Rajewsky N
- Subjects
- Animals, Cell Lineage, Cell Proliferation, Dentate Gyrus cytology, Gene Expression Regulation, Low Density Lipoprotein Receptor-Related Protein-2 deficiency, Low Density Lipoprotein Receptor-Related Protein-2 metabolism, Mice, Inbred C57BL, Models, Biological, Neural Stem Cells cytology, Neural Stem Cells metabolism, RNA metabolism, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism, Stem Cell Niche genetics, Aging genetics, Lateral Ventricles cytology, Neurogenesis genetics, Single-Cell Analysis, Transcriptome genetics
- Abstract
Neural stem cells (NSCs) contribute to plasticity and repair of the adult brain. Niches harboring NSCs regulate stem cell self-renewal and differentiation. We used comprehensive and untargeted single-cell RNA profiling to generate a molecular cell atlas of the largest germinal region of the adult mouse brain, the subventricular zone (SVZ). We characterized >20 neural and non-neural cell types and gained insights into the dynamics of neurogenesis by predicting future cell states based on computational analysis of RNA kinetics. Furthermore, we applied our single-cell approach to document decreased numbers of NSCs, reduced proliferation activity of progenitors, and perturbations in Wnt and BMP signaling pathways in mice lacking LRP2, an endocytic receptor required for SVZ maintenance. Our data provide a valuable resource to study adult neurogenesis and a proof of principle for the power of single-cell RNA sequencing to elucidate neural cell-type-specific alterations in loss-of-function models., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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28. Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs.
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Meyer K, Kirchner M, Uyar B, Cheng JY, Russo G, Hernandez-Miranda LR, Szymborska A, Zauber H, Rudolph IM, Willnow TE, Akalin A, Haucke V, Gerhardt H, Birchmeier C, Kühn R, Krauss M, Diecke S, Pascual JM, and Selbach M
- Subjects
- Amino Acid Motifs genetics, Amino Acid Sequence, Animals, Binding Sites, Calcium Channels, T-Type genetics, Calcium Channels, T-Type physiology, Carbohydrate Metabolism, Inborn Errors, Clathrin metabolism, Cytoplasm metabolism, Glucose Transporter Type 1 genetics, Glucose Transporter Type 1 metabolism, Humans, Inositol 1,4,5-Trisphosphate Receptors genetics, Inositol 1,4,5-Trisphosphate Receptors physiology, Intrinsically Disordered Proteins metabolism, Leucine metabolism, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Monosaccharide Transport Proteins deficiency, Mutation genetics, Peptides, Protein Binding, Proteomics methods, Glucose Transporter Type 1 physiology, Intrinsically Disordered Proteins genetics, Intrinsically Disordered Proteins physiology
- Abstract
Many disease-causing missense mutations affect intrinsically disordered regions (IDRs) of proteins, but the molecular mechanism of their pathogenicity is enigmatic. Here, we employ a peptide-based proteomic screen to investigate the impact of mutations in IDRs on protein-protein interactions. We find that mutations in disordered cytosolic regions of three transmembrane proteins (GLUT1, ITPR1, and CACNA1H) lead to an increased clathrin binding. All three mutations create dileucine motifs known to mediate clathrin-dependent trafficking. Follow-up experiments on GLUT1 (SLC2A1), the glucose transporter causative of GLUT1 deficiency syndrome, revealed that the mutated protein mislocalizes to intracellular compartments. Mutant GLUT1 interacts with adaptor proteins (APs) in vitro, and knocking down AP-2 reverts the cellular mislocalization and restores glucose transport. A systematic analysis of other known disease-causing variants revealed a significant and specific overrepresentation of gained dileucine motifs in structurally disordered cytosolic domains of transmembrane proteins. Thus, several mutations in disordered regions appear to cause "dileucineopathies.", (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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29. SORCS1 and SORCS3 control energy balance and orexigenic peptide production.
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Subkhangulova A, Malik AR, Hermey G, Popp O, Dittmar G, Rathjen T, Poy MN, Stumpf A, Beed PS, Schmitz D, Breiderhoff T, and Willnow TE
- Subjects
- Adiposity genetics, Age Factors, Animals, Body Composition genetics, Brain metabolism, Brain-Derived Neurotrophic Factor metabolism, Gene Expression, Genes, Reporter, Glucose metabolism, Homeostasis, Hypothalamus metabolism, Mice, Mice, Knockout, Models, Biological, Nerve Tissue Proteins metabolism, Neurons metabolism, Receptors, Cell Surface metabolism, Energy Metabolism genetics, Nerve Tissue Proteins genetics, Receptors, Cell Surface genetics
- Abstract
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., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2018
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30. Deletion of claudin-10 rescues claudin-16-deficient mice from hypomagnesemia and hypercalciuria.
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Breiderhoff T, Himmerkus N, Drewell H, Plain A, Günzel D, Mutig K, Willnow TE, Müller D, and Bleich M
- Subjects
- Animals, Calcium metabolism, Claudins genetics, Disease Models, Animal, Gene Deletion, Genetic Predisposition to Disease, Hypercalciuria genetics, Hypercalciuria metabolism, Hypercalciuria physiopathology, Kidney Tubules, Distal pathology, Kidney Tubules, Distal physiopathology, Loop of Henle pathology, Loop of Henle physiopathology, Magnesium metabolism, Magnesium Deficiency genetics, Magnesium Deficiency metabolism, Magnesium Deficiency physiopathology, Mice, Inbred C57BL, Mice, Knockout, Nephrocalcinosis genetics, Nephrocalcinosis metabolism, Nephrocalcinosis physiopathology, Nephrocalcinosis prevention & control, Phenotype, Sodium metabolism, Claudins deficiency, Hypercalciuria prevention & control, Kidney Tubules, Distal metabolism, Loop of Henle metabolism, Magnesium Deficiency prevention & control
- Abstract
The tight junction proteins claudin-10 and -16 are crucial for the paracellular reabsorption of cations along the thick ascending limb of Henle's loop in the kidney. In patients, mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, while mutations in CLDN10 impair kidney function. Mice lacking claudin-16 display magnesium and calcium wasting, whereas absence of claudin-10 results in hypermagnesemia and interstitial nephrocalcinosis. In order to study the functional interdependence of claudin-10 and -16 we generated double-deficient mice. These mice had normal serum magnesium and urinary excretion of magnesium and calcium and showed polyuria and sodium retention at the expense of increased renal potassium excretion, but no nephrocalcinosis. Isolated thick ascending limb tubules of double mutants displayed a complete loss of paracellular cation selectivity and functionality. Mice lacking both claudin-10 and -16 in the thick ascending limb recruited downstream compensatory mechanisms and showed hypertrophic distal convoluted tubules with changes in gene expression and phosphorylation of ion transporters in this segment, presumably triggered by the mild decrease in serum potassium. Thus, severe individual phenotypes in claudin-10 and claudin-16 knockout mice are corrected by the additional deletion of the other claudin., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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31. Cadm2 regulates body weight and energy homeostasis in mice.
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Yan X, Wang Z, Schmidt V, Gauert A, Willnow TE, Heinig M, and Poy MN
- Subjects
- Animals, Body Weight, Cell Adhesion Molecules metabolism, Cell Adhesion Molecules physiology, Cells, Cultured, Homeostasis, Humans, Hypothalamus metabolism, Insulin Resistance, Mice, Mice, Inbred C57BL, Obesity metabolism, Polymorphism, Single Nucleotide, Cell Adhesion Molecules genetics, Energy Metabolism, Obesity genetics
- Abstract
Objective: Obesity is strongly linked to genes regulating neuronal signaling and function, implicating the central nervous system in the maintenance of body weight and energy metabolism. Genome-wide association studies identified significant associations between body mass index (BMI) and multiple loci near Cell adhesion molecule2 (CADM2), which encodes a mediator of synaptic signaling enriched in the brain. Here we sought to further understand the role of Cadm2 in the pathogenesis of hyperglycemia and weight gain., Methods: We first analyzed Cadm2 expression in the brain of both human subjects and mouse models and subsequently characterized a loss-of-function mouse model of Cadm2 for alterations in glucose and energy homeostasis., Results: We show that the risk variant rs13078960 associates with increased CADM2 expression in the hypothalamus of human subjects. Increased Cadm2 expression in several brain regions of Lep
ob/ob mice was ameliorated after leptin treatment. Deletion of Cadm2 in obese mice (Cadm2/ob) resulted in reduced adiposity, systemic glucose levels, and improved insulin sensitivity. Cadm2-deficient mice exhibited increased locomotor activity, energy expenditure rate, and core body temperature identifying Cadm2 as a potent regulator of systemic energy homeostasis., Conclusions: Together these data illustrate that reducing Cadm2 expression can reverse several traits associated with the metabolic syndrome including obesity, insulin resistance, and impaired glucose homeostasis., (Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.)- Published
- 2018
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32. Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA.
- Author
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Eggert S, Gonzalez AC, Thomas C, Schilling S, Schwarz SM, Tischer C, Adam V, Strecker P, Schmidt V, Willnow TE, Hermey G, Pietrzik CU, Koo EH, and Kins S
- Subjects
- Amyloid beta-Protein Precursor chemistry, Amyloid beta-Protein Precursor genetics, Animals, Cell Line, Tumor, Cells, Cultured, Endosomes metabolism, Female, Golgi Apparatus metabolism, HEK293 Cells, HeLa Cells, Humans, LDL-Receptor Related Proteins genetics, Low Density Lipoprotein Receptor-Related Protein-1 genetics, Luminescent Proteins genetics, Luminescent Proteins metabolism, Male, Membrane Transport Proteins genetics, Mice, Inbred C57BL, Microscopy, Fluorescence, Protein Binding, Protein Multimerization, Protein Transport, Amyloid beta-Protein Precursor metabolism, LDL-Receptor Related Proteins metabolism, Low Density Lipoprotein Receptor-Related Protein-1 metabolism, Membrane Transport Proteins metabolism
- Abstract
Proteolytic cleavage of the amyloid precursor protein (APP) by α-, β- and γ-secretases is a determining factor in Alzheimer's disease (AD). Imbalances in the activity of all three enzymes can result in alterations towards pathogenic Aβ production. Proteolysis of APP is strongly linked to its subcellular localization as the secretases involved are distributed in different cellular compartments. APP has been shown to dimerize in cis-orientation, affecting Aβ production. This might be explained by different substrate properties defined by the APP oligomerization state or alternatively by altered APP monomer/dimer localization. We investigated the latter hypothesis using two different APP dimerization systems in HeLa cells. Dimerization caused a decreased localization of APP to the Golgi and at the plasma membrane, whereas the levels in the ER and in endosomes were increased. Furthermore, we observed via live cell imaging and biochemical analyses that APP dimerization affects its interaction with LRP1 and SorLA, suggesting that APP dimerization modulates its interplay with sorting molecules and in turn its localization and processing. Thus, pharmacological approaches targeting APP oligomerization properties might open novel strategies for treatment of AD.
- Published
- 2018
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33. SORLA attenuates EphA4 signaling and amyloid β-induced neurodegeneration.
- Author
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Huang TY, Zhao Y, Jiang LL, Li X, Liu Y, Sun Y, Piña-Crespo JC, Zhu B, Masliah E, Willnow TE, Pasquale EB, and Xu H
- Subjects
- Alzheimer Disease pathology, Animals, Ephrins pharmacology, Growth Cones drug effects, Growth Cones metabolism, HEK293 Cells, Humans, Ligands, Long-Term Potentiation drug effects, Membrane Transport Proteins chemistry, Membrane Transport Proteins genetics, Mice, Inbred BALB C, Mice, Transgenic, Mutation genetics, Nerve Degeneration metabolism, Protein Binding drug effects, Protein Domains, Receptors, LDL chemistry, Receptors, LDL genetics, Synapses drug effects, Synapses metabolism, Synapses pathology, Amyloid beta-Protein Precursor toxicity, LDL-Receptor Related Proteins metabolism, Membrane Transport Proteins metabolism, Nerve Degeneration pathology, Receptor, EphA4 metabolism, Receptors, LDL metabolism
- Abstract
Sortilin-related receptor with LDLR class A repeats (SORLA, SORL1, or LR11) is a genetic risk factor associated with Alzheimer's disease (AD). Although SORLA is known to regulate trafficking of the amyloid β (Aβ) precursor protein to decrease levels of proteotoxic Aβ oligomers, whether SORLA can counteract synaptic dysfunction induced by Aβ oligomers remains unclear. Here, we show that SORLA interacts with the EphA4 receptor tyrosine kinase and attenuates ephrinA1 ligand-induced EphA4 clustering and activation to limit downstream effects of EphA4 signaling in neurons. Consistent with these findings, SORLA transgenic mice, compared with WT mice, exhibit decreased EphA4 activation and redistribution to postsynaptic densities, with milder deficits in long-term potentiation and memory induced by Aβ oligomers. Importantly, we detected elevated levels of active EphA4 in human AD brains, where EphA4 activation is inversely correlated with SORLA/EphA4 association. These results demonstrate a novel role for SORLA as a physiological and pathological EphA4 modulator, which attenuates synaptotoxic EphA4 activation and cognitive impairment associated with Aβ-induced neurodegeneration in AD., (© 2017 Huang et al.)
- Published
- 2017
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34. Sorting receptor SORLA: cellular mechanisms and implications for disease.
- Author
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Schmidt V, Subkhangulova A, and Willnow TE
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amino Acid Sequence, Animals, Atherosclerosis genetics, Atherosclerosis metabolism, Atherosclerosis pathology, Brain metabolism, Brain pathology, Genetic Predisposition to Disease, Humans, LDL-Receptor Related Proteins analysis, Membrane Transport Proteins analysis, Nerve Growth Factors metabolism, Obesity genetics, Obesity metabolism, Obesity pathology, Protein Conformation, Protein Transport, Signal Transduction, LDL-Receptor Related Proteins genetics, LDL-Receptor Related Proteins metabolism, Membrane Transport Proteins genetics, Membrane Transport Proteins metabolism
- Abstract
Sorting-related receptor with A-type repeats (SORLA) is an intracellular sorting receptor that directs cargo proteins, such as kinases, phosphatases, and signaling receptors, to their correct location within the cell. The activity of SORLA assures proper function of cells and tissues, and receptor dysfunction is the underlying cause of common human malignancies, including Alzheimer's disease, atherosclerosis, and obesity. Here, we discuss the molecular mechanisms that govern sorting of SORLA and its cargo in multiple cell types, and why genetic defects in this receptor results in devastating diseases.
- Published
- 2017
- Full Text
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35. Nanotubes, the fast track to treatment of Dent disease?
- Author
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Willnow TE
- Subjects
- Animals, Disease Models, Animal, Kidney Tubules, Proximal, Mice, Nanotubes, Dent Disease, Fanconi Syndrome
- Abstract
Studies in mice have suggested bone marrow transplantation as a strategy to correct the endocytic dysfunction of the proximal tubules in renal Fanconi syndrome, yet the mode of action has remained mysterious. Using a mouse model of Dent disease, Gabriel et al. now show that rescue of the resorptive capacity in the diseased kidney involves cell-to-cell contact between engrafted and host cells via nanotubes, cellular projections that enable transfer of wild-type activity into mutant cells of the proximal tubule., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
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36. SorCS2 is required for BDNF-dependent plasticity in the hippocampus.
- Author
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Glerup S, Bolcho U, Mølgaard S, Bøggild S, Vaegter CB, Smith AH, Nieto-Gonzalez JL, Ovesen PL, Pedersen LF, Fjorback AN, Kjolby M, Login H, Holm MM, Andersen OM, Nyengaard JR, Willnow TE, Jensen K, and Nykjaer A
- Subjects
- Animals, Brain-Derived Neurotrophic Factor genetics, Brain-Derived Neurotrophic Factor metabolism, Hippocampus metabolism, Long-Term Potentiation physiology, Mice, Mice, Knockout, Neuronal Plasticity physiology, Neurons metabolism, Receptor, trkB metabolism, Receptors, Cell Surface genetics, Receptors, Cell Surface physiology, Receptors, N-Methyl-D-Aspartate metabolism, Signal Transduction drug effects, Receptors, Cell Surface metabolism, Receptors, Nerve Growth Factor metabolism
- Abstract
SorCS2 is a member of the Vps10p-domain receptor gene family receptors with critical roles in the control of neuronal viability and function. Several genetic studies have suggested SORCS2 to confer risk of bipolar disorder, schizophrenia and attention deficit-hyperactivity disorder. Here we report that hippocampal N-methyl-d-aspartate receptor-dependent synaptic plasticity is eliminated in SorCS2-deficient mice. This defect was traced to the ability of SorCS2 to form complexes with the neurotrophin receptor p75
NTR , required for pro-brain-derived neurotrophic factor (BDNF) to induce long-term depression, and with the BDNF receptor tyrosine kinase TrkB to elicit long-term potentiation. Although the interaction with p75NTR was static, SorCS2 bound to TrkB in an activity-dependent manner to facilitate its translocation to postsynaptic densities for synaptic tagging and maintenance of synaptic potentiation. Neurons lacking SorCS2 failed to respond to BDNF by TrkB autophosphorylation, and activation of downstream signaling cascades, impacting neurite outgrowth and spine formation. Accordingly, Sorcs2-/- mice displayed impaired formation of long-term memory, increased risk taking and stimulus seeking behavior, enhanced susceptibility to stress and impaired prepulse inhibition. Our results identify SorCS2 as an indispensable coreceptor for p75NTR and TrkB in hippocampal neurons and suggest SORCS2 as the link between proBDNF/BDNF signaling and mental disorders.- Published
- 2016
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37. SNX27 and SORLA Interact to Reduce Amyloidogenic Subcellular Distribution and Processing of Amyloid Precursor Protein.
- Author
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Huang TY, Zhao Y, Li X, Wang X, Tseng IC, Thompson R, Tu S, Willnow TE, Zhang YW, and Xu H
- Subjects
- Amyloidogenic Proteins metabolism, Animals, Cerebral Cortex cytology, Cerebral Cortex metabolism, Female, Gene Expression Regulation, HEK293 Cells, Humans, Mice, Neurons cytology, Protein Binding, Protein Transport, Amyloid biosynthesis, Amyloid beta-Protein Precursor metabolism, Membrane Transport Proteins metabolism, Neurons metabolism, Receptors, LDL metabolism, Sorting Nexins metabolism, Subcellular Fractions metabolism
- Abstract
Unlabelled: Proteolytic generation of amyloidogenic amyloid β (Aβ) fragments from the amyloid precursor protein (APP) significantly contributes to Alzheimer's disease (AD). Although amyloidogenic APP proteolysis can be affected by trafficking through genetically associated AD components such as SORLA, how SORLA functionally interacts with other trafficking components is yet unclear. Here, we report that SNX27, an endosomal trafficking/recycling factor and a negative regulator of the γ-secretase complex, binds to the SORLA cytosolic tail to form a ternary complex with APP. SNX27 enhances cell surface SORLA and APP levels in human cell lines and mouse primary neurons, and depletion of SNX27 or SORLA reduces APP endosome-to-cell surface recycling kinetics. SNX27 overexpression enhances the generation of cell surface APP cleavage products such as soluble alpha-APP C-terminal fragment (CTFα) in a SORLA-dependent manner. SORLA-mediated Aβ reduction is attenuated by downregulation of SNX27. This indicates that an SNX27/SORLA complex functionally interacts to limit APP distribution to amyloidogenic compartments, forming a non-amyloidogenic shunt to promote APP recycling to the cell surface., Significance Statement: Many genes have been identified as risk factors for Alzheimer's disease (AD), and a large proportion of these genes function to limit production or toxicity of the AD-associated amyloid β (Aβ) peptide. Whether and how these genes precisely operate to limit AD onset remains an important question. We identify binding and trafficking interactions between two of these factors, SORLA and SNX27, and demonstrate that SNX27 can direct trafficking of SORLA and the Aβ precursor APP to the cell surface to limit the production of Aβ. Diversion APP to the cell surface through modulation of this molecular complex may represent a complimentary strategy for future development in AD treatment., (Copyright © 2016 the authors 0270-6474/16/367996-16$15.00/0.)
- Published
- 2016
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38. SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity.
- Author
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Schmidt V, Schulz N, Yan X, Schürmann A, Kempa S, Kern M, Blüher M, Poy MN, Olivecrona G, and Willnow TE
- Subjects
- Adipose Tissue metabolism, Adult, Aged, Aged, 80 and over, Animals, Antigens, CD metabolism, Disease Models, Animal, Female, Gene Dosage, Genome-Wide Association Study, Glucose chemistry, Humans, Hydrolysis, Insulin metabolism, LDL-Receptor Related Proteins genetics, Male, Membrane Transport Proteins genetics, Mice, Mice, Knockout, Mice, Transgenic, Middle Aged, Risk Factors, Signal Transduction, Triglycerides metabolism, Young Adult, Adipocytes metabolism, Genetic Variation, LDL-Receptor Related Proteins metabolism, Membrane Transport Proteins metabolism, Obesity genetics, Receptor, Insulin metabolism, Receptors, LDL metabolism
- Abstract
In humans, genetic variation of sortilin-related receptor, L(DLR class) A repeats containing (SORL1), which encodes the intracellular sorting receptor SORLA, is a major genetic risk factor for familial and sporadic forms of Alzheimer's disease. Recent GWAS analysis has also associated SORL1 with obesity in humans and in mouse models, suggesting that this receptor may play a role in regulating metabolism. Here, using mouse models with genetic loss or tissue-specific overexpression of SORLA as well as data from obese human subjects, we observed a gene-dosage effect that links SORLA expression to obesity and glucose tolerance. Overexpression of human SORLA in murine adipose tissue blocked hydrolysis of triacylglycerides and caused excessive adiposity. In contrast, Sorl1 gene inactivation in mice accelerated breakdown of triacylglycerides in adipocytes and protected animals from diet-induced obesity. We then identified the underlying molecular mechanism whereby SORLA promotes insulin-induced suppression of lipolysis in adipocytes. Specifically, we determined that SORLA acts as a sorting factor for the insulin receptor (IR) that redirects internalized receptor molecules from endosomes to the plasma membrane, thereby enhancing IR surface expression and strengthening insulin signal reception in target cells. Our findings provide a molecular mechanism for the association of SORL1 with human obesity and confirm a genetic link between neurodegeneration and metabolism that converges on the receptor SORLA.
- Published
- 2016
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39. Calcineurin and Sorting-Related Receptor with A-Type Repeats Interact to Regulate the Renal Na⁺-K⁺-2Cl⁻ Cotransporter.
- Author
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Borschewski A, Himmerkus N, Boldt C, Blankenstein KI, McCormick JA, Lazelle R, Willnow TE, Jankowski V, Plain A, Bleich M, Ellison DH, Bachmann S, and Mutig K
- Subjects
- Animals, Male, Mice, Phosphorylation, Rats, Rats, Sprague-Dawley, Calcineurin physiology, Kidney metabolism, Membrane Transport Proteins physiology, Receptors, LDL physiology, Sodium-Potassium-Chloride Symporters physiology
- Abstract
The furosemide-sensitive Na(+)-K(+)-2Cl(-)-cotransporter (NKCC2) is crucial for NaCl reabsorption in kidney thick ascending limb (TAL) and drives the urine concentrating mechanism. NKCC2 activity is modulated by N-terminal phosphorylation and dephosphorylation. Serine-threonine kinases that activate NKCC2 have been identified, but less is known about phosphatases that deactivate NKCC2. Inhibition of calcineurin phosphatase has been shown to stimulate transport in the TAL and the distal convoluted tubule. Here, we identified NKCC2 as a target of the calcineurin Aβ isoform. Short-term cyclosporine administration in mice augmented the abundance of phospho-NKCC2, and treatment of isolated TAL with cyclosporine increased the chloride affinity and transport activity of NKCC2. Because sorting-related receptor with A-type repeats (SORLA) may affect NKCC2 phosphoregulation, we used SORLA-knockout mice to test whether SORLA is involved in calcineurin-dependent modulation of NKCC2. SORLA-deficient mice showed more calcineurin Aβ in the apical region of TAL cells and less NKCC2 phosphorylation and activity compared with littermate controls. In contrast, overexpression of SORLA in cultured cells reduced the abundance of endogenous calcineurin Aβ. Cyclosporine administration rapidly normalized the abundance of phospho-NKCC2 in SORLA-deficient mice, and a functional interaction between calcineurin Aβ and SORLA was further corroborated by binding assays in rat kidney extracts. In summary, we have shown that calcineurin Aβ and SORLA are key components in the phosphoregulation of NKCC2. These results may have clinical implications for immunosuppressive therapy using calcineurin inhibitors., (Copyright © 2016 by the American Society of Nephrology.)
- Published
- 2016
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40. LRP2 Acts as SHH Clearance Receptor to Protect the Retinal Margin from Mitogenic Stimuli.
- Author
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Christ A, Christa A, Klippert J, Eule JC, Bachmann S, Wallace VA, Hammes A, and Willnow TE
- Subjects
- Animals, Cell Proliferation drug effects, Embryo, Mammalian cytology, Embryo, Mammalian drug effects, Embryo, Mammalian metabolism, Female, Humans, Hydrophthalmos metabolism, Immunoenzyme Techniques, In Situ Hybridization, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons drug effects, Neurons metabolism, Retina drug effects, Retina embryology, Retina metabolism, Signal Transduction drug effects, Stem Cells cytology, Stem Cells drug effects, Stem Cells metabolism, Gene Expression Regulation, Developmental, Hedgehog Proteins metabolism, Hydrophthalmos pathology, Low Density Lipoprotein Receptor-Related Protein-2 physiology, Mitogens pharmacology, Neurons pathology, Retina pathology
- Abstract
During forebrain development, LRP2 promotes morphogen signaling as an auxiliary SHH receptor. However, in the developing retina, LRP2 assumes the opposing function, mediating endocytic clearance of SHH and antagonizing morphogen action. LRP2-mediated clearance prevents spread of SHH activity from the central retina into the retinal margin to protect quiescent progenitor cells in this niche from mitogenic stimuli. Loss of LRP2 in mice increases the sensitivity of the retinal margin for SHH, causing expansion of the retinal progenitor cell pool and hyperproliferation of this tissue. Our findings document the ability of LRP2 to act, in a context-dependent manner, as activator or inhibitor of the SHH pathway. Our current findings uncovered LRP2 activity as the molecular mechanism imposing quiescence of the retinal margin in the mammalian eye and suggest SHH-induced proliferation of the retinal margin as cause of the large eye phenotype observed in mouse models and patients with LRP2 defects., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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41. Distinct Functions for Anterograde and Retrograde Sorting of SORLA in Amyloidogenic Processes in the Brain.
- Author
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Dumanis SB, Burgert T, Caglayan S, Füchtbauer A, Füchtbauer EM, Schmidt V, and Willnow TE
- Subjects
- Amino Acid Motifs, Amino Acid Sequence, Amyloid beta-Peptides metabolism, Animals, Binding Sites, Cell Line, Endosomes metabolism, Female, Hippocampus cytology, LDL-Receptor Related Proteins metabolism, Lysosomes metabolism, Membrane Transport Proteins metabolism, Mice, Mice, Transgenic, Molecular Sequence Data, Mutagenesis, Site-Directed, Nerve Tissue Proteins metabolism, Protein Processing, Post-Translational, Protein Transport, RNA, Untranslated genetics, Recombinant Fusion Proteins metabolism, trans-Golgi Network metabolism, Adaptor Proteins, Vesicular Transport metabolism, Amyloid beta-Protein Precursor metabolism, Brain metabolism, LDL-Receptor Related Proteins physiology, Membrane Transport Proteins physiology
- Abstract
SORLA is a neuronal sorting receptor implicated both in sporadic and familial forms of AD. SORLA reduces the amyloidogenic burden by two mechanisms, either by rerouting internalized APP molecules from endosomes to the trans-Golgi network (TGN) to prevent proteolytic processing or by directing newly produced Aβ to lysosomes for catabolism. Studies in cell lines suggested that the interaction of SORLA with cytosolic adaptors retromer and GGA is required for receptor sorting to and from the TGN. However, the relevance of anterograde or retrograde trafficking for SORLA activity in vivo remained largely unexplored. Here, we generated mouse models expressing SORLA variants lacking binding sites for GGA or retromer to query this concept in the brain. Disruption of retromer binding resulted in a retrograde-sorting defect with accumulation of SORLA in endosomes and depletion from the TGN, and in an overall enhanced APP processing. In contrast, disruption of the GGA interaction did not impact APP processing but caused increased brain Aβ levels, a mechanism attributed to a defect in anterograde lysosomal targeting of Aβ. Our findings substantiated the significance of adaptor-mediated sorting for SORLA activities in vivo, and they uncovered that anterograde and retrograde sorting paths may serve discrete receptor functions in amyloidogenic processes., Significance Statement: SORLA is a sorting receptor that directs target proteins to distinct intracellular compartments in neurons. SORLA has been identified as a genetic risk factor for sporadic, but recently also for familial forms of AD. To confirm the relevance of SORLA sorting for AD processes in the brain, we generated mouse lines, which express trafficking mutants instead of the wild-type form of this receptor. Studying neuronal activities in these mutant mice, we dissected distinct trafficking routes for SORLA guided by two cytosolic adaptors termed GGA and retromer. We show that these sorting pathways serve discrete functions in control of amyloidogenic processes and may represent unique therapeutic targets to interfere with specific aspects of neurodegenerative processes in the diseased brain., (Copyright © 2015 the authors 0270-6474/15/3512703-11$15.00/0.)
- Published
- 2015
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42. Sorting receptor sortilin-a culprit in cardiovascular and neurological diseases.
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Carlo AS, Nykjaer A, and Willnow TE
- Subjects
- Adaptor Proteins, Vesicular Transport analysis, Animals, Humans, Protein Transport, Signal Transduction, Adaptor Proteins, Vesicular Transport metabolism, Cardiovascular Diseases metabolism, Neurodegenerative Diseases metabolism
- Abstract
Sortilin is a sorting receptor that directs target proteins, such as growth factors, signaling receptors, and enzymes, to their destined location in secretory or endocytic compartments of cells. The activity of sortilin is essential for proper function of not only neurons but also non-neuronal cell types, and receptor (dys)function emerges as a major cause of malignancies, including hypercholesterolemia, retinal degeneration, neuronal cell loss in stroke and spinal cord injury, or Alzheimer's disease and other neurodegenerative disorders. In this article, we describe the molecular mechanisms of sortilin action in protein sorting and signaling and how modulation of receptor function may offer novel therapeutic strategies for treatment of common diseases of the cardiovascular and nervous systems.
- Published
- 2014
- Full Text
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43. SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia.
- Author
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Glerup S, Olsen D, Vaegter CB, Gustafsen C, Sjoegaard SS, Hermey G, Kjolby M, Molgaard S, Ulrichsen M, Boggild S, Skeldal S, Fjorback AN, Nyengaard JR, Jacobsen J, Bender D, Bjarkam CR, Sørensen ES, Füchtbauer EM, Eichele G, Madsen P, Willnow TE, Petersen CM, and Nykjaer A
- Subjects
- Animals, Brain embryology, Brain-Derived Neurotrophic Factor metabolism, Corpus Striatum chemistry, Dopamine analysis, Dopamine metabolism, Frontal Lobe chemistry, Growth Cones metabolism, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons metabolism, Receptors, Nerve Growth Factor metabolism, Substantia Nigra metabolism, Ventral Tegmental Area metabolism, Apoptosis, Brain metabolism, Dopaminergic Neurons metabolism, Nerve Net metabolism, Nerve Tissue Proteins chemistry, Nerve Tissue Proteins metabolism, Receptors, Cell Surface chemistry, Receptors, Cell Surface metabolism, Schwann Cells metabolism
- Abstract
Balancing trophic and apoptotic cues is critical for development and regeneration of neuronal circuits. Here we identify SorCS2 as a proneurotrophin (proNT) receptor, mediating both trophic and apoptotic signals in conjunction with p75(NTR). CNS neurons, but not glia, express SorCS2 as a single-chain protein that is essential for proBDNF-induced growth cone collapse in developing dopaminergic processes. SorCS2- or p75(NTR)-deficient in mice caused reduced dopamine levels and metabolism and dopaminergic hyperinnervation of the frontal cortex. Accordingly, both knockout models displayed a paradoxical behavioral response to amphetamine reminiscent of ADHD. Contrary, in PNS glia, but not in neurons, proteolytic processing produced a two-chain SorCS2 isoform that mediated proNT-dependent Schwann cell apoptosis. Sciatic nerve injury triggered generation of two-chain SorCS2 in p75(NTR)-positive dying Schwann cells, with apoptosis being profoundly attenuated in Sorcs2(-/-) mice. In conclusion, we have demonstrated that two-chain processing of SorCS2 enables neurons and glia to respond differently to proneurotrophins., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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44. LRP2 mediates folate uptake in the developing neural tube.
- Author
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Kur E, Mecklenburg N, Cabrera RM, Willnow TE, and Hammes A
- Subjects
- Animals, Endocytosis, Folate Receptor 1 metabolism, Homeodomain Proteins biosynthesis, Homeodomain Proteins genetics, Low Density Lipoprotein Receptor-Related Protein-2 deficiency, Low Density Lipoprotein Receptor-Related Protein-2 genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neural Tube embryology, Reduced Folate Carrier Protein biosynthesis, Reduced Folate Carrier Protein genetics, Folic Acid metabolism, Low Density Lipoprotein Receptor-Related Protein-2 metabolism, Neural Tube metabolism
- Abstract
The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2) is a multifunctional cell-surface receptor expressed in the embryonic neuroepithelium. Loss of LRP2 in the developing murine central nervous system (CNS) causes impaired closure of the rostral neural tube at embryonic stage (E) 9.0. Similar neural tube defects (NTDs) have previously been attributed to impaired folate metabolism in mice. We therefore asked whether LRP2 might be required for the delivery of folate to neuroepithelial cells during neurulation. Uptake assays in whole-embryo cultures showed that LRP2-deficient neuroepithelial cells are unable to mediate the uptake of folate bound to soluble folate receptor 1 (sFOLR1). Consequently, folate concentrations are significantly reduced in Lrp2(-/-) embryos compared with control littermates. Moreover, the folic-acid-dependent gene Alx3 is significantly downregulated in Lrp2 mutants. In conclusion, we show that LRP2 is essential for cellular folate uptake in the developing neural tube, a crucial step for proper neural tube closure., (© 2014. Published by The Company of Biologists Ltd.)
- Published
- 2014
- Full Text
- View/download PDF
45. SORLA-dependent and -independent functions for PACS1 in control of amyloidogenic processes.
- Author
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Burgert T, Schmidt V, Caglayan S, Lin F, Füchtbauer A, Füchtbauer EM, Nykjaer A, Carlo AS, and Willnow TE
- Subjects
- Amino Acid Sequence, Animals, Brain enzymology, Cathepsin B biosynthesis, Cell Line, Tumor, Gene Knockdown Techniques, Humans, LDL-Receptor Related Proteins chemistry, Membrane Transport Proteins chemistry, Mice, Mice, Transgenic, Molecular Sequence Data, Neurons metabolism, Protein Binding, Protein Interaction Domains and Motifs, Protein Transport, Receptor, IGF Type 2 metabolism, Vesicular Transport Proteins chemistry, Vesicular Transport Proteins genetics, Amyloid beta-Protein Precursor metabolism, LDL-Receptor Related Proteins physiology, Membrane Transport Proteins physiology, Vesicular Transport Proteins metabolism
- Abstract
Sorting-related receptor with A-type repeats (SORLA) is a sorting receptor for the amyloid precursor protein (APP) that prevents breakdown of APP into Aβ peptides, a hallmark of Alzheimer's disease (AD). Several cytosolic adaptors have been shown to interact with the cytoplasmic domain of SORLA, thereby controlling intracellular routing of SORLA/APP complexes in cell lines. However, the relevance of adaptor-mediated sorting of SORLA for amyloidogenic processes in vivo remained unexplored. We focused on the interaction of SORLA with phosphofurin acidic cluster sorting protein 1 (PACS1), an adaptor that shuttles proteins between the trans-Golgi network (TGN) and endosomes. By studying PACS1 knockdown in neuronal cell lines and investigating transgenic mice expressing a PACS1-binding-defective mutant form of SORLA, we found that disruption of SORLA and PACS1 interaction results in the inability of SORLA/APP complexes to sort to the TGN in neurons and in increased APP processing in the brain. Loss of PACS1 also impairs the proper expression of the cation-independent mannose 6-phosphate receptor and its target cathepsin B, a protease that breaks down Aβ. Thus, our data identified the importance of PACS1-dependent protein sorting for amyloidogenic-burden control via both SORLA-dependent and SORLA-independent mechanisms.
- Published
- 2013
- Full Text
- View/download PDF
46. Sortilin-related receptor SORCS3 is a postsynaptic modulator of synaptic depression and fear extinction.
- Author
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Breiderhoff T, Christiansen GB, Pallesen LT, Vaegter C, Nykjaer A, Holm MM, Glerup S, and Willnow TE
- Subjects
- Animals, Behavior, Animal, Carrier Proteins metabolism, Cell Cycle Proteins, Cell Line, Evoked Potentials, Gene Expression, Hippocampus metabolism, Humans, Male, Memory, Mice, Mice, Knockout, Nerve Tissue Proteins genetics, Neuronal Plasticity physiology, Neurons metabolism, Nuclear Proteins metabolism, Post-Synaptic Density metabolism, Protein Binding, Protein Transport, Receptors, Cell Surface genetics, Extinction, Psychological physiology, Fear physiology, Long-Term Synaptic Depression physiology, Nerve Tissue Proteins metabolism, Receptors, Cell Surface metabolism
- Abstract
SORCS3 is an orphan receptor of the VPS10P domain receptor family, a group of sorting and signaling receptors central to many pathways in control of neuronal viability and function. SORCS3 is highly expressed in the CA1 region of the hippocampus, but the relevance of this receptor for hippocampal activity remained absolutely unclear. Here, we show that SORCS3 localizes to the postsynaptic density and that loss of receptor activity in gene-targeted mice abrogates NMDA receptor-dependent and -independent forms of long-term depression (LTD). Consistent with a loss of synaptic retraction, SORCS3-deficient mice suffer from deficits in behavioral activities associated with hippocampal LTD, particularly from an accelerated extinction of fear memory. A possible molecular mechanism for SORCS3 in synaptic depression was suggested by targeted proteomics approaches that identified the ability of SORCS3 to functionally interact with PICK1, an adaptor that sorts glutamate receptors at the postsynapse. Faulty localization of PICK1 in SORCS3-deficient neurons argues for altered glutamate receptor trafficking as the cause of altered synaptic plasticity in the SORCS3-deficient mouse model. In conclusion, our studies have identified a novel function for VPS10P domain receptors in control of synaptic depression and suggest SORCS3 as a novel factor modulating aversive memory extinction.
- Published
- 2013
- Full Text
- View/download PDF
47. SORLA-mediated trafficking of TrkB enhances the response of neurons to BDNF.
- Author
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Rohe M, Hartl D, Fjorback AN, Klose J, and Willnow TE
- Subjects
- Animals, Animals, Newborn, Brain-Derived Neurotrophic Factor pharmacology, Cell Line, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Huntington Disease metabolism, Huntington Disease physiopathology, LDL-Receptor Related Proteins genetics, Male, Membrane Glycoproteins genetics, Membrane Transport Proteins genetics, Mice, Mice, Transgenic, Neurons cytology, Neurons drug effects, Primary Cell Culture, Protein Transport, Protein-Tyrosine Kinases genetics, Receptor, trkB, Receptors, LDL genetics, Signal Transduction, Synapses drug effects, Synapses genetics, Brain-Derived Neurotrophic Factor metabolism, Huntington Disease genetics, LDL-Receptor Related Proteins metabolism, Membrane Glycoproteins metabolism, Membrane Transport Proteins metabolism, Neurons metabolism, Protein-Tyrosine Kinases metabolism, Receptors, LDL metabolism
- Abstract
Stimulation of neurons with brain-derived neurotrophic factor (BDNF) results in robust induction of SORLA, an intracellular sorting receptor of the VPS10P domain receptor gene family. However, the relevance of SORLA for BDNF-induced neuronal responses has not previously been investigated. We now demonstrate that SORLA is a sorting factor for the tropomyosin-related kinase receptor B (TrkB) that facilitates trafficking of this BDNF receptor between synaptic plasma membranes, post-synaptic densities, and cell soma, a step critical for neuronal signal transduction. Loss of SORLA expression results in impaired neuritic transport of TrkB and in blunted response to BDNF in primary neurons; and it aggravates neuromotoric deficits caused by low BDNF activity in a mouse model of Huntington's disease. Thus, our studies revealed a key role for SORLA in mediating BDNF trophic signaling by regulating the intracellular location of TrkB.
- Published
- 2013
- Full Text
- View/download PDF
48. Sorting receptor SORLA--a trafficking path to avoid Alzheimer disease.
- Author
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Willnow TE and Andersen OM
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid Precursor Protein Secretases genetics, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Protein Precursor genetics, Brain pathology, Cell Membrane pathology, Cell Movement, Endosomes metabolism, Endosomes pathology, Gene Expression Regulation, Humans, LDL-Receptor Related Proteins genetics, Membrane Transport Proteins genetics, Neurons pathology, Protein Transport, Proteolysis, Signal Transduction, trans-Golgi Network metabolism, trans-Golgi Network pathology, Alzheimer Disease metabolism, Amyloid beta-Protein Precursor metabolism, Brain metabolism, Cell Membrane metabolism, LDL-Receptor Related Proteins metabolism, Membrane Transport Proteins metabolism, Neurons metabolism
- Abstract
Excessive proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid β peptides (Aβ) by secretases in the brain is a molecular cause of Alzheimer disease (AD). According to current concepts, the complex route whereby APP moves between the secretory compartment, the cell surface and endosomes to encounter the various secretases determines its processing fate. However, the molecular mechanisms that control the intracellular trafficking of APP in neurons and their contribution to AD remain poorly understood. Here, we describe the functional elucidation of a new sorting receptor SORLA that emerges as a central regulator of trafficking and processing of APP. SORLA interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network and early endosomes, thereby restricting delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. Defects in SORLA and its interacting adaptors result in transport defects and enhanced amyloidogenic processing of APP, and represent important risk factors for AD in patients. As discussed here, these findings uncovered a unique regulatory pathway for the control of neuronal protein transport, and provide clues as to why defects in this pathway cause neurodegenerative disease.
- Published
- 2013
- Full Text
- View/download PDF
49. Soluble alpha-APP (sAPPalpha) regulates CDK5 expression and activity in neurons.
- Author
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Hartl D, Klatt S, Roch M, Konthur Z, Klose J, Willnow TE, and Rohe M
- Subjects
- Animals, Cells, Cultured, Electrophoresis, Gel, Two-Dimensional, Mass Spectrometry, Mice, Mice, Inbred BALB C, Amyloid beta-Protein Precursor pharmacology, Cyclin-Dependent Kinase 5 metabolism, Neurons drug effects, Neurons metabolism
- Abstract
A growing body of evidence suggests a role for soluble alpha-amyloid precursor protein (sAPPalpha) in pathomechanisms of Alzheimer disease (AD). This cleavage product of APP was identified to have neurotrophic properties. However, it remained enigmatic what proteins, targeted by sAPPalpha, might be involved in such neuroprotective actions. Here, we used high-resolution two-dimensional polyacrylamide gel electrophoresis to analyze proteome changes downstream of sAPPalpha in neurons. We present evidence that sAPPalpha regulates expression and activity of CDK5, a kinase that plays an important role in AD pathology. We also identified the cytoprotective chaperone ORP150 to be induced by sAPPalpha as part of this protective response. Finally, we present functional evidence that the sAPPalpha receptor SORLA is essential to mediate such molecular functions of sAPPalpha in neurons.
- Published
- 2013
- Full Text
- View/download PDF
50. The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-β peptide in the brain.
- Author
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Carlo AS, Gustafsen C, Mastrobuoni G, Nielsen MS, Burgert T, Hartl D, Rohe M, Nykjaer A, Herz J, Heeren J, Kempa S, Petersen CM, and Willnow TE
- Subjects
- Animals, Apolipoproteins E metabolism, Astrocytes metabolism, Mice, Plaque, Amyloid metabolism, Adaptor Proteins, Vesicular Transport metabolism, Amyloid beta-Peptides metabolism, Brain metabolism, Low Density Lipoprotein Receptor-Related Protein-1 metabolism, Neurons metabolism
- Abstract
Apolipoprotein E (APOE) is the major risk factor for sporadic Alzheimer's disease. Among other functions, APOE is proposed to sequester neurotoxic amyloid-β (Aβ) peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors. Still, the receptors involved in this process remain controversial. Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Also, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/Aβ complexes despite proper expression of other APOE receptors. Despite higher than normal brain APOE levels, sortilin-deficient animals display anomalies in brain lipid metabolism (e.g., accumulation of sulfatides) seen in APOE-deficient mice, indicating functional deficiency in cellular APOE uptake pathways. Together, our findings identified sortilin as an essential neuronal pathway for APOE-containing lipoproteins in vivo and suggest an intriguing link between Aβ catabolism and pro-neurotrophin signaling converging on this receptor.
- Published
- 2013
- Full Text
- View/download PDF
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