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Jean Mazella - One of the best experts on this subject based on the ideXlab platform.
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Sortilin neurotensin receptor 3 and its derived peptides in depression
2021Co-Authors: Jean Mazella, Marc Borsotto, Catherine HeurteauxAbstract:Abstract Sortilin, also called neurotensin (NTS) receptor-3 (NTSR3), displays a role of a multifunctional protein that is the consequence of its particular posttranslational and cellular properties. Sortilin is synthesized under a precursor form that is cleaved to generate a functional protein and a 44-amino acid peptide (named PE) at the level of late Golgi compartments. When present at the plasma membrane, Sortilin is shedded by matrix metalloproteases leading to the release of a soluble form of the protein. Interestingly, in resting cells, Sortilin is differentially distributed, 90% intracellularly and only 10% at the cell surface where the protein can play a role of receptor or coreceptor. Intracellular Sortilin is involved in the sorting of other proteins to the plasma membrane and/or to the lysosomal pathway. Finally, the role of Sortilin in depression comes from its interaction with the two-pore potassium channel TREK-1 that allows its sorting to the plasma membrane and also by the fact that PE and its shorter analog spadin are selective and specific blockers of this channel. The chapter summarizes the various roles of mature Sortilin, soluble Sortilin, and Sortilin-derived peptides in the cellular and physiological mechanisms that are involved to detect or to treat depression.
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the involvement of Sortilin ntsr3 in depression as the progenitor of spadin and its role in the membrane expression of trek 1
Frontiers in Pharmacology, 2019Co-Authors: Jean Mazella, Marc Borsotto, Catherine HeurteauxAbstract:The molecular identification of Sortilin, also called neurotensin receptor-3, from three different biochemical approaches already predicted the involvement of the protein in numerous biological and cellular functions. The first important observation was that Sortilin is synthesized as a precursor that is converted to a mature protein after cleavage by the protein convertase furin in late Golgi compartments. This maturation leads to the formation of a 44 amino acid peptide, the propeptide (PE). The release of this peptide when matured Sortilin reached the plasma membrane remained to be demonstrated. Sortilin has been also shown to be shedded by matrix metalloproteases releasing a large extracellular fragment identified as soluble Sortilin. Therefore, Sortilin has been shown to interact with several proteins and receptors confirming its role in the sorting of cellular components to the plasma membrane and/or to the lysosomal pathway. Interestingly, Sortilin physically interacts with the two pore domain potassium channel TREK-1 and the PE as well as its synthetic analogue spadin is able to block the activation of TREK-1 highlighting their role in the depression pathology. The present review describes the advance of research that led to these results and how both the soluble form of Sortilin and the Sortilin-derived propeptides have been detected in human serum and whose levels are affected in patients with major depressive disorder (MDD). The use of spadin as an antidepressant and the further role of soluble Sortilin and of Sortilin-derived propeptides as potential biomarkers during depression statement and/or remission of the pathology are considered and discussed in this review.
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The Involvement of Sortilin/NTSR3 in Depression as the Progenitor of Spadin and Its Role in the Membrane Expression of TREK-1.
Frontiers in pharmacology, 2019Co-Authors: Jean Mazella, Marc Borsotto, Catherine HeurteauxAbstract:The molecular identification of Sortilin, also called neurotensin receptor-3, from three different biochemical approaches already predicted the involvement of the protein in numerous biological and cellular functions. The first important observation was that Sortilin is synthesized as a precursor that is converted to a mature protein after cleavage by the protein convertase furin in late Golgi compartments. This maturation leads to the formation of a 44 amino acid peptide, the propeptide (PE). The release of this peptide when matured Sortilin reached the plasma membrane remained to be demonstrated. Sortilin has been also shown to be shedded by matrix metalloproteases releasing a large extracellular fragment identified as soluble Sortilin. Therefore, Sortilin has been shown to interact with several proteins and receptors confirming its role in the sorting of cellular components to the plasma membrane and/or to the lysosomal pathway. Interestingly, Sortilin physically interacts with the two pore domain potassium channel TREK-1 and the PE as well as its synthetic analogue spadin is able to block the activation of TREK-1 highlighting their role in the depression pathology. The present review describes the advance of research that led to these results and how both the soluble form of Sortilin and the Sortilin-derived propeptides have been detected in human serum and whose levels are affected in patients with major depressive disorder (MDD). The use of spadin as an antidepressant and the further role of soluble Sortilin and of Sortilin-derived propeptides as potential biomarkers during depression statement and/or remission of the pathology are considered and discussed in this review.
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The Involvement of Sortilin/NTSR3 in Depression as the Progenitor of Spadin and Its Role in the Membrane Expression of TREK-1
Frontiers Media S.A., 2019Co-Authors: Jean Mazella, Marc Borsotto, Catherine HeurteauxAbstract:The molecular identification of Sortilin, also called neurotensin receptor-3, from three different biochemical approaches already predicted the involvement of the protein in numerous biological and cellular functions. The first important observation was that Sortilin is synthesized as a precursor that is converted to a mature protein after cleavage by the protein convertase furin in late Golgi compartments. This maturation leads to the formation of a 44 amino acid peptide, the propeptide (PE). The release of this peptide when matured Sortilin reached the plasma membrane remained to be demonstrated. Sortilin has been also shown to be shedded by matrix metalloproteases releasing a large extracellular fragment identified as soluble Sortilin. Therefore, Sortilin has been shown to interact with several proteins and receptors confirming its role in the sorting of cellular components to the plasma membrane and/or to the lysosomal pathway. Interestingly, Sortilin physically interacts with the two pore domain potassium channel TREK-1 and the PE as well as its synthetic analog spadin is able to block the activation of TREK-1 highlighting their role in the depression pathology. The present review describes the advance of research that led to these results and how both the soluble form of Sortilin and the Sortilin-derived PE have been detected in human serum and whose levels are affected in patients with major depressive disorder (MDD). The use of spadin as an antidepressant and the further role of soluble Sortilin and of Sortilin-derived PE as potential biomarkers during depression statement and/or remission of the pathology are considered and discussed in this review
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focal adhesion kinase dependent role of the soluble form of neurotensin receptor 3 Sortilin in colorectal cancer cell dissociation
International Journal of Molecular Sciences, 2016Co-Authors: Sophie Berauddufour, Christelle Devader, Fabienne Massa, Morgane Roulot, Thierry Coppola, Jean MazellaAbstract:The aim of the present review is to unravel the mechanisms of action of the soluble form of the neurotensin (NT) receptor-3 (NTSR3), also called Sortilin, in numerous physiopathological processes including cancer development, cardiovascular diseases and depression. Sortilin/NTSR3 is a transmembrane protein thought to exert multiple functions both intracellularly and at the level of the plasma membrane. The Sortilin/NTSR3 extracellular domain is released by shedding from all the cells expressing the protein. Although the existence of the soluble form of Sortilin/NTSR3 (sSortilin/NTSR3) has been evidenced for more than 10 years, the studies focusing on the role of this soluble protein at the mechanistic level remain rare. Numerous cancer cells, including colonic cancer cells, express the receptor family of neurotensin (NT), and particularly Sortilin/NTSR3. This review aims to summarize the functional role of sSortilin/NTSR3 characterized in the colonic cancer cell line HT29. This includes mechanisms involving signaling cascades through focal adhesion kinase (FAK), a key pathway leading to the weakening of cell–cell and cell–extracellular matrix adhesions, a series of events which could be responsible for cancer metastasis. Finally, some future approaches targeting the release of sNTSR3 through the inhibition of matrix metalloproteases (MMPs) are suggested.
Anders Nykjaer - One of the best experts on this subject based on the ideXlab platform.
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Prions amplify through degradation of the VPS10P sorting receptor Sortilin.
PLoS pathogens, 2017Co-Authors: Keiji Uchiyama, Anders Nykjaer, Mitsuru Tomita, Masashi Yano, Junji Chida, Hideyuki Hara, Nandita Rani Das, Suehiro SakaguchiAbstract:Prion diseases are a group of fatal neurodegenerative disorders caused by prions, which consist mainly of the abnormally folded isoform of prion protein, PrPSc. A pivotal pathogenic event in prion disease is progressive accumulation of prions, or PrPSc, in brains through constitutive conformational conversion of the cellular prion protein, PrPC, into PrPSc. However, the cellular mechanism by which PrPSc is progressively accumulated in prion-infected neurons remains unknown. Here, we show that PrPSc is progressively accumulated in prion-infected cells through degradation of the VPS10P sorting receptor Sortilin. We first show that Sortilin interacts with PrPC and PrPSc and sorts them to lysosomes for degradation. Consistently, Sortilin-knockdown increased PrPSc accumulation in prion-infected cells. In contrast, overexpression of Sortilin reduced PrPSc accumulation in prion-infected cells. These results indicate that Sortilin negatively regulates PrPSc accumulation in prion-infected cells. The negative role of Sortilin in PrPSc accumulation was further confirmed in Sortilin-knockout mice infected with prions. The infected mice had accelerated prion disease with early accumulation of PrPSc in their brains. Interestingly, Sortilin was reduced in prion-infected cells and mouse brains. Treatment of prion-infected cells with lysosomal inhibitors, but not proteasomal inhibitors, increased the levels of Sortilin. Moreover, Sortilin was reduced following PrPSc becoming detectable in cells after infection with prions. These results indicate that PrPSc accumulation stimulates Sortilin degradation in lysosomes. Taken together, these results show that PrPSc accumulation of itself could impair the Sortilin-mediated sorting of PrPC and PrPSc to lysosomes for degradation by stimulating lysosomal degradation of Sortilin, eventually leading to progressive accumulation of PrPSc in prion-infected cells.
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Soluble Sortilin is present in excess and positively correlates with progranulin in CSF of aging individuals.
Experimental gerontology, 2016Co-Authors: Simon Molgaard, Claus Munck Petersen, Anders Nykjaer, Ditte Demontis, Alexandra M. Nicholson, Nicole A. Finch, Ronald C. Petersen, Rosa Rademakers, Simon GlerupAbstract:Mutations in progranulin are a major cause of frontotemporal lobe degeneration (FTLD). Hence, plasma progranulin is an attractive biomarker in FTLD but poorly reflects levels in cerebrospinal fluid (CSF), suggesting tissue-specific regulation of progranulin levels. Sortilin was recently identified as a progranulin scavenger receptor that destines it for lysosomal degradation. Proteolysis or alternative splicing generates soluble Sortilin variants that retain progranulin binding and potentially functions as a decoy receptor. In the present study, we analyzed soluble Sortilin and progranulin in plasma and CSF in 341 aging individuals. We found that soluble Sortilin exists in CSF in ten-fold molar excess compared to progranulin and observed a highly significant positive correlation between soluble Sortilin and progranulin levels in CSF but not in plasma. However, carriers of the minor allele of SNP rs646776 in SORT1 encoding Sortilin displayed significantly increased soluble Sortilin and reduced progranulin specifically in plasma but not in CSF. Taken together, our findings suggest that soluble Sortilin may affect progranulin levels in both a tissue-specific and genotype-dependent manner.
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Sortilin mediates vascular calcification via its recruitment into extracellular vesicles
The Journal of clinical investigation, 2016Co-Authors: Claudia Goettsch, Joshua D Hutcheson, Masanori Aikawa, Mads Kjolby, Anders Nykjaer, Hiroshi Iwata, Tan Pham, Maximillian A. Rogers, Thomas Michel, Manabu ShibasakiAbstract:Vascular calcification is a common feature of major cardiovascular diseases. Extracellular vesicles participate in the formation of microcalcifications that are implicated in atherosclerotic plaque rupture; however, the mechanisms that regulate formation of calcifying extracellular vesicles remain obscure. Here, we have demonstrated that Sortilin is a key regulator of smooth muscle cell (SMC) calcification via its recruitment to extracellular vesicles. Sortilin localized to calcifying vessels in human and mouse atheromata and participated in formation of microcalcifications in SMC culture. Sortilin regulated the loading of the calcification protein tissue nonspecific alkaline phosphatase (TNAP) into extracellular vesicles, thereby conferring its calcification potential. Furthermore, SMC calcification required Rab11-dependent trafficking and FAM20C/casein kinase 2-dependent C-terminal phosphorylation of Sortilin. In a murine model, Sort1-deficiency reduced arterial calcification but did not affect bone mineralization. Additionally, transfer of Sortilin-deficient BM cells to irradiated atherosclerotic mice did not affect vascular calcification, indicating a primary role of SMC-derived Sortilin. Together, the results of this study identify Sortilin phosphorylation as a potential therapeutic target for ectopic calcification/microcalcification and may clarify the mechanism that underlies the genetic association between the SORT1 gene locus and coronary artery calcification.
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ABSENCE OF A THYROID PHENOTYPE IN Sortilin-DEFICIENT MICE.
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 2015Co-Authors: Simonetta Lisi, Claus Munck Petersen, Peder Madsen, Anders Nykjaer, R. Botta, Francesco Latrofa, Paolo Vitti, Michele MarinòAbstract:ABSTRACT Objective: The Vps10p family member Sortilin is expressed in thyroid epithelial cells where it contributes to recycling of the thyroid hormone precursor thyroglobulin (Tg), a process that is thought to render hormone release more effective. Here we investigated the functional impact of Sortilin in the thyroid gland using Sortilin-deficient mice. Methods: We measured free T4, thyroid-stimulating hormone (TSH) and Tg serum levels and studied thyroid morphology in 14 Sortilin-deficient (Sort1)−/−and 12 wildtype (WT) mice. Results: Serum free T4 levels did not differ between Sort1−/−and WT females but were significantly lower in Sort1−/−males compared with WT (P = .0424). Neither serum TSH nor Tg levels differed between Sort1−/−and WT mice, regardless of sex. On the same line, no thyroid histology differences were observed. Conclusion: Our findings seem to exclude a role of Sortilin in thyroid hormone secretion, although it is possible that the absence of Sortilin may result in a thyroid phenotype if...
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Targeting Sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis
The Journal of clinical investigation, 2014Co-Authors: Martin Bødtker Mortensen, Mads Kjolby, Anders Nykjaer, Stine Gunnersen, Jakob Vejby Larsen, Johan Palmfeldt, Erling Falk, Jacob F. BentzonAbstract:Genome-wide association studies have identified a link between genetic variation at the human chromosomal locus 1p13.3 and coronary artery disease. The gene encoding Sortilin (SORT1) has been implicated as the causative gene within the locus, as Sortilin regulates hepatic lipoprotein metabolism. Here we demonstrated that Sortilin also directly affects atherogenesis, independent of its regulatory role in lipoprotein metabolism. In a mouse model of atherosclerosis, deletion of Sort1 did not alter plasma cholesterol levels, but reduced the development of both early and late atherosclerotic lesions. We determined that Sortilin is a high-affinity receptor for the proinflammatory cytokines IL-6 and IFN-γ. Moreover, macrophages and Th1 cells (both of which mediate atherosclerotic plaque formation) lacking Sortilin had reduced secretion of IL-6 and IFN-γ, but not of other measured cytokines. Transfer of Sortilin-deficient BM into irradiated atherosclerotic mice reduced atherosclerosis and systemic markers of inflammation. Together, these data demonstrate that Sortilin influences cytokine secretion and that targeting Sortilin in immune cells attenuates inflammation and reduces atherosclerosis.
Claus Munck Petersen - One of the best experts on this subject based on the ideXlab platform.
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Soluble Sortilin is present in excess and positively correlates with progranulin in CSF of aging individuals.
Experimental gerontology, 2016Co-Authors: Simon Molgaard, Claus Munck Petersen, Anders Nykjaer, Ditte Demontis, Alexandra M. Nicholson, Nicole A. Finch, Ronald C. Petersen, Rosa Rademakers, Simon GlerupAbstract:Mutations in progranulin are a major cause of frontotemporal lobe degeneration (FTLD). Hence, plasma progranulin is an attractive biomarker in FTLD but poorly reflects levels in cerebrospinal fluid (CSF), suggesting tissue-specific regulation of progranulin levels. Sortilin was recently identified as a progranulin scavenger receptor that destines it for lysosomal degradation. Proteolysis or alternative splicing generates soluble Sortilin variants that retain progranulin binding and potentially functions as a decoy receptor. In the present study, we analyzed soluble Sortilin and progranulin in plasma and CSF in 341 aging individuals. We found that soluble Sortilin exists in CSF in ten-fold molar excess compared to progranulin and observed a highly significant positive correlation between soluble Sortilin and progranulin levels in CSF but not in plasma. However, carriers of the minor allele of SNP rs646776 in SORT1 encoding Sortilin displayed significantly increased soluble Sortilin and reduced progranulin specifically in plasma but not in CSF. Taken together, our findings suggest that soluble Sortilin may affect progranulin levels in both a tissue-specific and genotype-dependent manner.
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Increased serum levels of Sortilin are associated with depression and correlated with BDNF and VEGF.
Translational psychiatry, 2015Co-Authors: Henriette N. Buttenschøn, Claus Munck Petersen, Simon Molgaard, Ditte Demontis, Mathias Kaas, Betina Elfving, Camilla Gustafsen, Linda Kaerlev, Anders D. Børglum, Ole MorsAbstract:Neurotrophic factors have been investigated in relation to depression. The aim of the present study was to widen this focus to Sortilin, a receptor involved in neurotrophic signalling. The serum Sortilin level was investigated in 152 individuals with depression and 216 control individuals, and eight genetic markers located within the SORT1 gene were successfully analysed for association with depression. Genotyping was performed using the Sequenom MassARRAY platform. All the individuals returned a questionnaire and participated in a semi-structured diagnostic interview. Sortilin levels were measured by immunoassay, and potential determinants of the serum Sortilin level were assessed by generalized linear models. Serum levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were measured in previous studies. We identified a significant increase of serum Sortilin levels in depressed individuals compared with controls (P=0.0002) and significant positive correlation between serum Sortilin levels and the corresponding levels of BDNF and VEGF. None of the genotyped SNPs were associated with depression. Additional analyses showed that the serum Sortilin level was influenced by several other factors. Alcohol intake and body mass index, as well as depression, serum BDNF and serum VEGF were identified as predictors of serum Sortilin levels in our final multivariate model. In conclusion, the results suggest a role of circulating Sortilin in depression which may relate to altered activity of neurotrophic factors.
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ABSENCE OF A THYROID PHENOTYPE IN Sortilin-DEFICIENT MICE.
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 2015Co-Authors: Simonetta Lisi, Claus Munck Petersen, Peder Madsen, Anders Nykjaer, R. Botta, Francesco Latrofa, Paolo Vitti, Michele MarinòAbstract:ABSTRACT Objective: The Vps10p family member Sortilin is expressed in thyroid epithelial cells where it contributes to recycling of the thyroid hormone precursor thyroglobulin (Tg), a process that is thought to render hormone release more effective. Here we investigated the functional impact of Sortilin in the thyroid gland using Sortilin-deficient mice. Methods: We measured free T4, thyroid-stimulating hormone (TSH) and Tg serum levels and studied thyroid morphology in 14 Sortilin-deficient (Sort1)−/−and 12 wildtype (WT) mice. Results: Serum free T4 levels did not differ between Sort1−/−and WT females but were significantly lower in Sort1−/−males compared with WT (P = .0424). Neither serum TSH nor Tg levels differed between Sort1−/−and WT mice, regardless of sex. On the same line, no thyroid histology differences were observed. Conclusion: Our findings seem to exclude a role of Sortilin in thyroid hormone secretion, although it is possible that the absence of Sortilin may result in a thyroid phenotype if...
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σ1b adaptin regulates adipogenesis by mediating the sorting of Sortilin in adipose tissue
Journal of Cell Science, 2014Co-Authors: Jennifer Baltes, Claus Munck Petersen, Jakob Vejby Larsen, Karthikeyan Radhakrishnan, Constanze Geumann, Manuel Kratzke, Peter SchuAbstract:ABSTRACT Here, we describe altered sorting of Sortilin in adipocytes deficient for the σ1B-containing AP-1 complex, leading to the inhibition of adipogenesis. The AP-1 complex mediates protein sorting between the trans-Golgi network and endosomes. Vertebrates express three AP1 σ1 subunit isoforms – σ1A, σ1B and σ1C (also known as AP1S1, AP1S2 and AP1S3, respectively). σ1B-deficient mice display impaired recycling of synaptic vesicles and lipodystrophy. Here, we show that Sortilin is overexpressed in adipose tissue from σ1B−/− mice, and that its overexpression in wild-type cells is sufficient to suppress adipogenesis. σ1B-specific binding of Sortilin requires the Sortilin DxxD-x12-DSxxxL motif. σ1B deficiency does not lead to a block of Sortilin transport out of a specific organelle, but the fraction that reaches lysosomes is reduced. Sortilin binds to the receptor DLK1, an inhibitor of adipocyte differentiation, and the overexpression of Sortilin prevents DLK1 downregulation, leading to enhanced inhibition of adipogenesis. DLK1 and Sortilin expression are not increased in the brain tissue of σ1B−/− mice, although this is the tissue with the highest expression of σ1B and Sortilin. Thus, adipose-tissue-specific and σ1B-dependent routes for the transport of Sortilin exist and are involved in the regulation of adipogenesis and adipose-tissue mass.
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distribution of nts3 receptor Sortilin mrna and protein in the rat central nervous system
The Journal of Comparative Neurology, 2003Co-Authors: Philippe Sarret, Morten Nielsen, Claus Munck Petersen, Jean Mazella, Pascale Krzywkowski, Laura Segal, Thomas Stroh, Alain BeaudetAbstract:The neurotensin (NT) receptor, NTS3, originally identified as the intracellular sorting protein Sortilin, is a member of a recently discovered family of receptors characterized by a single transmembrane domain. The present study provides the first comprehensive description of the distribution of NTS3/Sortilin mRNA and protein in adult rat brain using in situ hybridization and immunocytochemistry. Both NTS3/Sortilin mRNA and immunoreactivity displayed a widespread distribution throughout the brain. High levels of NTS3/Sortilin expression and immunoreactivity were found in neuronal cell bodies and dendrites of allocortical areas such as the piriform cortex and hippocampus. Regions expressing both high levels of NTS3/Sortilin mRNA and protein also included several neocortical areas, the islands of Calleja, medial and lateral septal nuclei, amygdaloid nuclei, thalamic nuclei, the supraoptic nucleus, the substantia nigra, and the Purkinje cell layer of the cerebellar cortex. In the brainstem, all cranial nerve motor nuclei were strongly labeled. NTS3/Sortilin mRNA and immunoreactivity were also detected over oligodendrocytes in major fiber tracts. Subcellularly, NTS3/Sortilin was predominantly concentrated over intracytoplasmic membrane-bound organelles. Many of the areas exhibiting high levels of NTS3/Sortilin (e.g., olfactory cortex, medial septum, and periaqueductal gray) have been documented to contain high concentrations of NT nerve cell bodies and axons, supporting the concept that NTS3/Sortilin may play a role in NT sorting and/or signaling. Other areas (e.g., hippocampal CA fields, cerebellar cortex, and cranial nerve motor nuclei), however, are NT-negative, suggesting that NTS3/Sortilin also exerts functions unrelated to NT signaling.
Carlos R. Morales - One of the best experts on this subject based on the ideXlab platform.
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the intracellular domain of Sortilin interacts with amyloid precursor protein and regulates its lysosomal and lipid raft trafficking
PLOS ONE, 2013Co-Authors: Miao Yang, Balaji Virassamy, Swarna Lekha Vijayaraj, Yoon Lim, Khalil Saadipour, Yanjiang Wang, Yanchuang Han, Jinhua Zhong, Carlos R. MoralesAbstract:The processing of Amyloid precursor protein (APP) is multifaceted, comprising of protein transport, internalization and sequential proteolysis. However, the exact mechanism of APP intracellular trafficking and distribution remains unclear. To determine the interaction between Sortilin and APP and the effect of Sortilin on APP trafficking and processing, we studied the binding site and its function by mapping experiments, colocalization, coimmunoprecipitation and sucrose gradient fractionation. We identified for the first time that Sortilin interacts with APP at both N- and C-terminal regions. The Sortilin-FLVHRY (residues 787–792) and APP-NPTYKFFE (residues 759–766) motifs are crucial for the C-terminal interaction. We also found that lack of the FLVHRY motif reduces APP lysosomal targeting and increases APP distribution in lipid rafts in co-transfected HEK293 cells. These results are consistent with our in vivo data where Sortilin knockout mice showed a decrease of APP lysosomal distribution and an increase of APP in lipid rafts. We further confirmed that overexpression of Sortilin-FLVHRY mutants failed to rescue the lysosomal degradation of APP. Thus, our data suggests that Sortilin is implicated in APP lysosomal and lipid raft targeting via its carboxyl-terminal F/YXXXXF/Y motif. Our study provides new molecular insights into APP trafficking and processing.
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abstract 5 Sortilin regulates hepatic vldl secretion and ldl uptake in a lysosome dependent manner
Arteriosclerosis Thrombosis and Vascular Biology, 2012Co-Authors: Alanna Strong, Carlos R. Morales, Qiurong Ding, Andrew C Edmondson, Sumeet A Khetarpal, Sissel Lundkatz, Michael C Phillips, Kiran Musunuru, Daniel J RaderAbstract:Sortilin, the protein product of the SORT1 gene, is a multi-ligand sorting receptor involved in Golgi to lysosome and plasma membrane to lysosome protein trafficking. Genome wide association studies for lipid traits have identified the 1p13 locus harboring the SORT1 gene as strongly associated both with plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) risk in humans. Adeno-associated virus (AAV)-mediated hepatic Sortilin overexpression in LDL receptor deficient mice reduced plasma cholesterol by 30% at two weeks ( n = 6 mice per group, P = 0.02), with a concomitant reduction in LDL-C. In vivo VLDL production studies demonstrated a 50% reduction in the VLDL triglyceride secretion rate ( P = 0.007) and a 50% reduction in apoB secretion ( P = 0.02) with Sortilin overexpression. In vivo LDL turnover studies demonstrated a 3-fold increase in the LDL fractional catabolic rate (FCR) with Sortilin overexpression ( n = 6 mice per group, P = 0.00002). Sortilin deficiency both alone and on an LDL receptor deficient background led to a 40% and 50% reduction in FCR ( n = 6 mice per group, P = 0.002 and P = 0.01). The effect of Sortilin on both VLDL secretion and LDL turnover is dependent on the ability of Sortilin to traffic to the lysosome, as Sortilin mutants that cannot traffic to the lysosome do not affect VLDL secretion or LDL uptake in vivo or in vitro . Surface plasmon reasonance demonstrated a high affinity interaction between Sortilin and the apoB in LDL particles at physiological pH with a Kd of ∼2 nM, and this affinity virtually disappears at the acidic lysosomal pH. In sum, these data are consistent with a model in which Sortilin binds apoB-containing lipoprotein particles in the Golgi apparatus and at the plasma membrane and traffics them to the endolysosomal compartment for degradation, thereby reducing VLDL secretion and facilitating LDL uptake, explaining the strong association of hepatic Sortilin overexpression in humans with reduced plasma cholesterol.
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The interactomics of Sortilin: an ancient lysosomal receptor evolving new functions.
Histology and histopathology, 2009Co-Authors: Maryssa Canuel, Yuan Libin, Carlos R. MoralesAbstract:The delivery of soluble lysosomal proteins to the lysosomes is dependent primarily on the mannose 6-phosphate receptor (MPR). The MPR has been demonstrated to attain the early endosomes via a process that requires the interaction of its cytosolic domain with the GGA and AP-1 adaptor proteins. Additionally, the MPR can be recycled back to the trans-Golgi network (TGN) through its interaction with the retromer complex. Interestingly, in I-cell disease (ICD), in which the MPR pathway is non-functional, many soluble lysosomal proteins continue to traffic to the lysosomes. This observation led to the discovery that Sortilin is responsible for the MPR-independent targeting of the sphingolipid activator proteins (SAPs) and acid sphingomyelinase (ASM). More recently, our laboratory has tested the hypothesis that Sortilin is also capable of sorting a variety of cathepsins that exhibit varying degrees of MPR-independent transport. We have demonstrated that the transport of cathepsin D is partially dependent upon Sortilin, that cathepsin H requires Sortilin, and that cathepsins K and L attain the lysosomes in a Sortilin-independent fashion. As a type-1 receptor, Sortilin also has numerous cytosolic binding partners. It has been observed that like the MPR, the anterograde trafficking of Sortilin and its cargo require both GGAs and AP-1. Similarly, the retrograde recycling pathway of Sortilin also involves an interaction with retromer through a YXXphi site in the cytosolic tail of Sortilin. In conclusion, the cytosolic domains of Sortilin and MPR possess a high degree of functional homology and both receptors share a conserved trafficking mechanism.
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Sortilin and prosaposin localize to detergent-resistant membrane microdomains.
Experimental cell research, 2008Co-Authors: Maryssa Canuel, Nihar Bhattacharyya, Alejandro Balbis, Libin Yuan, Carlos R. MoralesAbstract:Most soluble lysosomal hydrolases are sorted in the trans-Golgi network (TGN) and delivered to the lysosomes by the mannose 6-phosphate receptor (M6PR). However, the non-enzymic sphingolipid activator protein (SAP), prosaposin, as well as certain soluble lysosomal hydrolases, is sorted and trafficked to the lysosomes by Sortilin. Based on previous results demonstrating that prosaposin requires sphingomyelin to be targeted to the lysosomes, we hypothesized that Sortilin and its ligands are found in detergent-resistant membranes (DRMs). To test this hypothesis we have analyzed DRM fractions and demonstrated the presence of Sortilin and its ligand, prosaposin. Our results showed that both the M6PR and its cargo, cathepsin B, were also present in DRMs. Cathepsin H has previously been demonstrated to interact with Sortilin, while cathepsin D interacts with both Sortilin and the M6PR. Both of these soluble lysosomal proteins were also found in DRM fractions. Using Sortilin shRNA we have showed that prosaposin is localized to DRM fractions only in the presence of Sortilin. These observations suggest that in addition to interacting with the same adaptor proteins, such as GGAs, AP-1 and retromer, both Sortilin and the M6PR localize to similar membrane platforms, and that prosaposin must interact with Sortilin to be recruited to DRMs.
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Sortilin mediates the lysosomal targeting of cathepsins D and H.
Biochemical and biophysical research communications, 2008Co-Authors: Maryssa Canuel, Ann Korkidakis, Kristin J. Konnyu, Carlos R. MoralesAbstract:Delivery of soluble lysosomal proteins to the lysosomes is dependent primarily on the mannose 6-phosphate receptor (M6PR). However, in I-cell disease (ICD), in which the M6PR pathway is non-functional, some soluble lysosomal proteins continue to traffic to the lysosomes. In this paper, we tested the hypothesis that cathepsins D and H, two soluble proteases that exhibit M6PR-independent trafficking, are targeted to the lysosomes by Sortilin. Using a dominant-negative Sortilin construct and small interfering RNA (siRNA) we demonstrated that while cathepsin D transport is partially dependent upon Sortilin, cathepsin H requires exclusively Sortilin for its transport to the lysosomes. Our results suggest that Sortilin functions as an alternative sorting receptor to the M6PR for these soluble hydrolases.
Catherine Heurteaux - One of the best experts on this subject based on the ideXlab platform.
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Sortilin neurotensin receptor 3 and its derived peptides in depression
2021Co-Authors: Jean Mazella, Marc Borsotto, Catherine HeurteauxAbstract:Abstract Sortilin, also called neurotensin (NTS) receptor-3 (NTSR3), displays a role of a multifunctional protein that is the consequence of its particular posttranslational and cellular properties. Sortilin is synthesized under a precursor form that is cleaved to generate a functional protein and a 44-amino acid peptide (named PE) at the level of late Golgi compartments. When present at the plasma membrane, Sortilin is shedded by matrix metalloproteases leading to the release of a soluble form of the protein. Interestingly, in resting cells, Sortilin is differentially distributed, 90% intracellularly and only 10% at the cell surface where the protein can play a role of receptor or coreceptor. Intracellular Sortilin is involved in the sorting of other proteins to the plasma membrane and/or to the lysosomal pathway. Finally, the role of Sortilin in depression comes from its interaction with the two-pore potassium channel TREK-1 that allows its sorting to the plasma membrane and also by the fact that PE and its shorter analog spadin are selective and specific blockers of this channel. The chapter summarizes the various roles of mature Sortilin, soluble Sortilin, and Sortilin-derived peptides in the cellular and physiological mechanisms that are involved to detect or to treat depression.
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the involvement of Sortilin ntsr3 in depression as the progenitor of spadin and its role in the membrane expression of trek 1
Frontiers in Pharmacology, 2019Co-Authors: Jean Mazella, Marc Borsotto, Catherine HeurteauxAbstract:The molecular identification of Sortilin, also called neurotensin receptor-3, from three different biochemical approaches already predicted the involvement of the protein in numerous biological and cellular functions. The first important observation was that Sortilin is synthesized as a precursor that is converted to a mature protein after cleavage by the protein convertase furin in late Golgi compartments. This maturation leads to the formation of a 44 amino acid peptide, the propeptide (PE). The release of this peptide when matured Sortilin reached the plasma membrane remained to be demonstrated. Sortilin has been also shown to be shedded by matrix metalloproteases releasing a large extracellular fragment identified as soluble Sortilin. Therefore, Sortilin has been shown to interact with several proteins and receptors confirming its role in the sorting of cellular components to the plasma membrane and/or to the lysosomal pathway. Interestingly, Sortilin physically interacts with the two pore domain potassium channel TREK-1 and the PE as well as its synthetic analogue spadin is able to block the activation of TREK-1 highlighting their role in the depression pathology. The present review describes the advance of research that led to these results and how both the soluble form of Sortilin and the Sortilin-derived propeptides have been detected in human serum and whose levels are affected in patients with major depressive disorder (MDD). The use of spadin as an antidepressant and the further role of soluble Sortilin and of Sortilin-derived propeptides as potential biomarkers during depression statement and/or remission of the pathology are considered and discussed in this review.
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The Involvement of Sortilin/NTSR3 in Depression as the Progenitor of Spadin and Its Role in the Membrane Expression of TREK-1.
Frontiers in pharmacology, 2019Co-Authors: Jean Mazella, Marc Borsotto, Catherine HeurteauxAbstract:The molecular identification of Sortilin, also called neurotensin receptor-3, from three different biochemical approaches already predicted the involvement of the protein in numerous biological and cellular functions. The first important observation was that Sortilin is synthesized as a precursor that is converted to a mature protein after cleavage by the protein convertase furin in late Golgi compartments. This maturation leads to the formation of a 44 amino acid peptide, the propeptide (PE). The release of this peptide when matured Sortilin reached the plasma membrane remained to be demonstrated. Sortilin has been also shown to be shedded by matrix metalloproteases releasing a large extracellular fragment identified as soluble Sortilin. Therefore, Sortilin has been shown to interact with several proteins and receptors confirming its role in the sorting of cellular components to the plasma membrane and/or to the lysosomal pathway. Interestingly, Sortilin physically interacts with the two pore domain potassium channel TREK-1 and the PE as well as its synthetic analogue spadin is able to block the activation of TREK-1 highlighting their role in the depression pathology. The present review describes the advance of research that led to these results and how both the soluble form of Sortilin and the Sortilin-derived propeptides have been detected in human serum and whose levels are affected in patients with major depressive disorder (MDD). The use of spadin as an antidepressant and the further role of soluble Sortilin and of Sortilin-derived propeptides as potential biomarkers during depression statement and/or remission of the pathology are considered and discussed in this review.
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The Involvement of Sortilin/NTSR3 in Depression as the Progenitor of Spadin and Its Role in the Membrane Expression of TREK-1
Frontiers Media S.A., 2019Co-Authors: Jean Mazella, Marc Borsotto, Catherine HeurteauxAbstract:The molecular identification of Sortilin, also called neurotensin receptor-3, from three different biochemical approaches already predicted the involvement of the protein in numerous biological and cellular functions. The first important observation was that Sortilin is synthesized as a precursor that is converted to a mature protein after cleavage by the protein convertase furin in late Golgi compartments. This maturation leads to the formation of a 44 amino acid peptide, the propeptide (PE). The release of this peptide when matured Sortilin reached the plasma membrane remained to be demonstrated. Sortilin has been also shown to be shedded by matrix metalloproteases releasing a large extracellular fragment identified as soluble Sortilin. Therefore, Sortilin has been shown to interact with several proteins and receptors confirming its role in the sorting of cellular components to the plasma membrane and/or to the lysosomal pathway. Interestingly, Sortilin physically interacts with the two pore domain potassium channel TREK-1 and the PE as well as its synthetic analog spadin is able to block the activation of TREK-1 highlighting their role in the depression pathology. The present review describes the advance of research that led to these results and how both the soluble form of Sortilin and the Sortilin-derived PE have been detected in human serum and whose levels are affected in patients with major depressive disorder (MDD). The use of spadin as an antidepressant and the further role of soluble Sortilin and of Sortilin-derived PE as potential biomarkers during depression statement and/or remission of the pathology are considered and discussed in this review
