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Lindahl, Ulf
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Publications (10 of 37) Show all publications
Kjellén, L. & Lindahl, U. (2018). Specificity of glycosaminoglycan-protein interactions. Current opinion in structural biology, 50, 101-108
Open this publication in new window or tab >>Specificity of glycosaminoglycan-protein interactions
2018 (English)In: Current opinion in structural biology, ISSN 0959-440X, E-ISSN 1879-033X, Vol. 50, p. 101-108Article in journal (Refereed) Published
Abstract [en]

Glycosaminoglycans (GAGs) interact with a variety of proteins with important functions in development and homeostasis. Most of these proteins bind to heparin in vitro, a highly sulfated GAG species, although heparan sulfate and/or chondroitin/dermatan sulfate are more frequent physiological ligands. Binding affinity and specificity are determined by charge distribution, mainly due to sulfate and carboxylate groups and by GAG chain conformation. Interactions may be nonspecific, essentially reflecting charge density or highly specific, dependent on rare GAG-structural features. Yet other GAG epitopes bind protein ligands with intermediate specificity and variable affinity. Studies of heparan sulfate biosynthesis point to stochastic but strictly regulated, cell-specific polymer modification. Together, these features allow for graded modulation of protein functional response.

Place, publisher, year, edition, pages
CURRENT BIOLOGY LTD, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-364480 (URN)10.1016/j.sbi.2017.12.011 (DOI)000443661300015 ()29455055 (PubMedID)
Available from: 2018-10-30 Created: 2018-10-30 Last updated: 2018-10-30Bibliographically approved
Ramachandra, R., Namburi, R. B., Dupont, S., Ortega-Martinez, O., Thorndyke, M., Lindahl, U. & Spillmann, D. (2017). A Potential Role for Chondroitin Sulfate/Dermatan Sulfate in Arm Regeneration in Amphiura filiformis.. Glycobiology, 27(5), 438-449
Open this publication in new window or tab >>A Potential Role for Chondroitin Sulfate/Dermatan Sulfate in Arm Regeneration in Amphiura filiformis.
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2017 (English)In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 27, no 5, p. 438-449Article in journal (Refereed) Published
Abstract [en]

Glycosaminoglycans (GAGs), such as chondroitin sulfate (CS) and dermatan sulfate (DS) from various vertebrate and invertebrate sources are known to be involved in diverse cellular mechanisms during repair and regenerative processes. Recently, we have identified CS/DS as the major GAG in the brittlestar Amphiura filiformis, with high proportions of di- and tri-O-sulfated disaccharide units. As this echinoderm is known for its exceptional regeneration capacity, we aimed to explore the role of these GAG chains during A. filiformis arm regeneration. Analysis of CS/DS chains during the regeneration process revealed an increase in the proportion of the tri-O-sulfated disaccharides. Conversely, treatment of A. filiformis with sodium chlorate, a potent inhibitor of sulfation reactions in GAG biosynthesis, resulted in a significant reduction in arm growth rates with total inhibition at concentrations higher than 5 mM. Differentiation was less impacted by sodium chlorate exposure or even slightly increased at 1-2 mM. Based on the structural changes observed during arm regeneration we identified chondroitin synthase, chondroitin-4-O-sulfotransferase 2 and dermatan-4-O-sulfotransferase as candidate genes and sought to correlate their expression with the expression of the A. filiformis orthologue of bone morphogenetic factors, AfBMP2/4. Quantitative amplification by real-time PCR indicated increased expression of chondroitin synthase and chondroitin-4-O-sulfotransferase 2, with a corresponding increase in AfBMP2/4 during regeneration relative to nonregenerating controls. Our findings suggest that proper sulfation of GAGs is important for A. filiformis arm regeneration and that these molecules may participate in mechanisms controlling cell proliferation.

Keywords
Echinoderm, Brittlestars, Chondroitin sulfate, Dermatan sulfate, Sodium chlorate
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-178991 (URN)10.1093/glycob/cwx010 (DOI)000401003500007 ()28130266 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish Research Council FormasWenner-Gren Foundations
Available from: 2012-08-10 Created: 2012-08-06 Last updated: 2017-06-19Bibliographically approved
O'Callaghan, P., Li, J.-P., Lannfelt, L., Lindahl, U. & Zhang, X. (2015). Microglial Heparan Sulfate Proteoglycans Facilitate the Cluster-of-Differentiation 14 (CD14)/Toll-like Receptor 4 (TLR4)-Dependent Inflammatory Response. Journal of Biological Chemistry, 290(24), 14904-14914
Open this publication in new window or tab >>Microglial Heparan Sulfate Proteoglycans Facilitate the Cluster-of-Differentiation 14 (CD14)/Toll-like Receptor 4 (TLR4)-Dependent Inflammatory Response
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2015 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 24, p. 14904-14914Article in journal (Refereed) Published
Abstract [en]

Microglia rapidly mount an inflammatory response to pathogens in the central nervous system (CNS). Heparan sulfate proteoglycans (HSPGs) have been attributed various roles in inflammation. To elucidate the relevance of microglial HSPGs in a pro-inflammatory response we isolated microglia from mice overexpressing heparanase (Hpa-tg), the HS-degrading endoglucuronidase, and challenged them with lipopolysaccharide (LPS), a bacterial endotoxin. Prior to LPS-stimulation, the LPS-receptor cluster-of-differentiation 14 (CD14) and Toll-like receptor 4 (TLR4; essential for the LPS response) were similarly expressed in Ctrl and Hpa-tg microglia. However, compared with Ctrl microglia, Hpa-tg cells released significantly less tumor necrosis factor-α (TNFα), essentially failed to up-regulate interleukin-1β (IL1β) and did not initiate synthesis of proCD14. Isolated primary astroyctes expressed TLR4, but notably lacked CD14 and in contrast to microglia, LPS challenge induced a similar TNFα response in Ctrl and Hpa-tg astrocytes, while neither released IL1β. The astrocyte TNFα-induction was thus attributed to CD14-independent TLR4 activation and was unaffected by the cells HS status. Equally, the suppressed LPS-response in Hpa-tg microglia indicated a loss of CD14-dependent TLR4 activation, suggesting that microglial HSPGs facilitate this process. Indeed, confocal microscopy confirmed interactions between microglial HS and CD14 in LPS-stimulated microglia and a potential HS-binding motif in CD14 was identified. We conclude that microglial HSPGs facilitate CD14-dependent TLR4 activation and that heparanase can modulate this mechanism.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-257815 (URN)10.1074/jbc.M114.634337 (DOI)000356177300010 ()25869127 (PubMedID)
Funder
Swedish Research Council, 2003-5546
Available from: 2015-07-09 Created: 2015-07-09 Last updated: 2017-12-04Bibliographically approved
Lindahl, U. (2014). A personal voyage through the proteoglycan field. Matrix Biology, 35, 3-7
Open this publication in new window or tab >>A personal voyage through the proteoglycan field
2014 (English)In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 35, p. 3-7Article in journal (Refereed) Published
Abstract [en]

The concept of "proteoglycans" as discrete molecules surfaced some 40 years ago, out of previously muddled notions of the extracellular matrix. Core proteins were gradually recognized as molecular entities, distinct with regard to location, substitution with glycosaminoglycan (GAG) chains and biological function. This development is surveyed, with brief outline of methodological approaches, biosynthesis, and functional aspects. Special emphasis is given to the impact of genomics on the field. Some outstanding unresolved issues are emphasized, including regulation of GAG biosynthesis and the specificity of GAG-protein interactions.

Keywords
Heparan sulfate, Chondroitin sulfate, GAGosome, Core proteins, Glycosaminoglycan chain, Glycosaminoglycan biosynthesis, Glycosaminoglycan-protein interactions
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-228818 (URN)10.1016/j.matbio.2014.01.001 (DOI)000337556500002 ()24463261 (PubMedID)
Available from: 2014-07-22 Created: 2014-07-22 Last updated: 2017-12-05Bibliographically approved
O'Callaghan, P., Noborn, F., Sehlin, D., Li, J.-p., Lannfelt, L., Lindahl, U. & Zhang, X. (2014). Apolipoprotein E increases cell association of amyloid-β 40 through heparan sulfate and LRP1 dependent pathways. Amyloid: Journal of Protein Folding Disorders, 21(2), 76-87
Open this publication in new window or tab >>Apolipoprotein E increases cell association of amyloid-β 40 through heparan sulfate and LRP1 dependent pathways
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2014 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 21, no 2, p. 76-87Article in journal (Refereed) Published
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-168315 (URN)10.3109/13506129.2013.879643 (DOI)000336146700002 ()
Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2017-12-08
Ramachandra, R., Namburi, R. B., Ortega-Martinez, O., Shi, X., Zaia, J., Dupont, S. T., . . . Spillmann, D. (2014). Brittlestars contain highly sulfated chondroitin sulfates/dermatan sulfates that promote fibroblast growth factor 2-induced cell signaling. Glycobiology, 24(2), 195-207
Open this publication in new window or tab >>Brittlestars contain highly sulfated chondroitin sulfates/dermatan sulfates that promote fibroblast growth factor 2-induced cell signaling
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2014 (English)In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 24, no 2, p. 195-207Article in journal (Refereed) Published
Abstract [en]

Glycosaminoglycans (GAGs) isolated from brittlestars, Echinodermata class Ophiuroidea, were characterized, as part of attempts to understand the evolutionary development of these polysaccharides. A population of chondroitin sulfate/dermatan sulfate (CS/DS) chains with a high overall degree of sulfation and hexuronate epimerization was the major GAG found, whereas heparan sulfate (HS) was below detection level. Enzymatic digestion with different chondroitin lyases revealed exceptionally high proportions of di- and trisulfated CS/DS disaccharides. The latter unit appears much more abundant in one of four individual species of brittlestars, Amphiura filiformis, than reported earlier in other marine invertebrates. The brittlestar CS/DS was further shown to bind to growth factors such as fibroblast growth factor 2 and to promote FGF-stimulated cell signaling in GAG-deficient cell lines in a manner similar to that of heparin. These findings point to a potential biological role for the highly sulfated invertebrate GAGs, similar to those ascribed to HS in vertebrates.

Keywords
Brittlestar, Chodroitin sulfate, Dermatan sulfate, Fibroblast growth factor-2
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-178989 (URN)10.1093/glycob/cwt100 (DOI)000330839300009 ()
Available from: 2012-08-10 Created: 2012-08-06 Last updated: 2017-12-07Bibliographically approved
Lindahl, U. & Kjellén, L. (2013). Pathophysiology of heparan sulphate: many diseases, few drugs. Journal of Internal Medicine, 273(6), 555-571
Open this publication in new window or tab >>Pathophysiology of heparan sulphate: many diseases, few drugs
2013 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 273, no 6, p. 555-571Article, review/survey (Refereed) Published
Abstract [en]

Heparan sulphate (HS) polysaccharides are covalently attached to the core proteins of various proteoglycans at cell surfaces and in the extracellular matrix. They are composed of alternating units of hexuronic acid and glucosamine, with sulphate substituents in complex and variable yet cell-specific patterns. Whereas HS is produced by virtually all cells in the body, heparin, a highly sulphated HS variant, is confined to connective-tissue-type mast cells. The polysaccharides interact with a multitude of proteins, mainly through ionic binding, and thereby control key processes in development and homoeostasis. Similar interactions also implicate HS in various pathophysiological settings, including cancer, amyloid diseases, infectious diseases, inflammatory conditions and some developmental disorders. Prospects for the development of HS-based drugs, which are still largely unrealized, are discussed.

Keywords
amyloid, cancer, heparanase, heparin, inflammation, malaria, sulphation pattern
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-202469 (URN)10.1111/joim.12061 (DOI)000318986100003 ()
Available from: 2013-07-01 Created: 2013-06-24 Last updated: 2017-12-06Bibliographically approved
Kusche-Gullberg, M., Nybakken, K., Perrimon, N. & Lindahl, U. (2012). Drosophila heparan sulfate: a novel design. Journal of Biological Chemistry, 287(26), 21950-21956
Open this publication in new window or tab >>Drosophila heparan sulfate: a novel design
2012 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 26, p. 21950-21956Article in journal (Refereed) Published
Abstract [en]

Heparan sulfate (HS) proteoglycans play critical roles in a wide variety of biological processes such as growth factor signaling, cell adhesion, wound healing, and tumor metastasis. Functionally important interactions between HS and a variety of proteins depend on specific structural features within the HS chains. The fruit fly (Drosophila melanogaster) is frequently applied as a model organism to study HS function in development. Previous structural studies of Drosophila HS have been restricted to disaccharide composition, without regard to the arrangement of saccharide domains typically found in vertebrate HS. Here, we biochemically characterized Drosophila HS by selective depolymerization with nitrous acid. Analysis of the generated saccharide products revealed a novel HS design, involving a peripheral, extended, presumably single, N-sulfated domain linked to an N-acetylated sequence contiguous with the linkage to core protein. The N-sulfated domain may be envisaged as a heparin structure of unusually low O-sulfate content.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-194282 (URN)10.1074/jbc.M112.350389 (DOI)000306418600034 ()22556423 (PubMedID)
Available from: 2013-02-12 Created: 2013-02-12 Last updated: 2018-05-31Bibliographically approved
Karlsson-Lindahl, L., Schmidt, L., Haage, D., Hansson, C., Taube, M., Egeciouglu, E., . . . Dickson, S. L. (2012). Heparanase Affects Food Intake and Regulates Energy Balance in Mice. PLoS ONE, 7(3), e34313
Open this publication in new window or tab >>Heparanase Affects Food Intake and Regulates Energy Balance in Mice
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. e34313-Article in journal (Refereed) Published
Abstract [en]

Mutation of the melanocortin-receptor 4 (MC4R) is the most frequent cause of severe obesity in humans. Binding of agouti-related peptide (AgRP) to MC4R involves the co-receptor syndecan-3, a heparan sulfate proteoglycan. The proteoglycan can be structurally modified by the enzyme heparanase. Here we tested the hypothesis that heparanase plays a role in food intake behaviour and energy balance regulation by analysing body weight, body composition and food intake in genetically modified mice that either lack or overexpress heparanase. We also assessed food intake and body weight following acute central intracerebroventricular administration of heparanase; such treatment reduced food intake in wildtype mice, an effect that was abolished in mice lacking MC4R. By contrast, heparanase knockout mice on a high-fat diet showed increased food intake and maturity-onset obesity, with up to a 40% increase in body fat. Mice overexpressing heparanase displayed essentially the opposite phenotypes, with a reduced fat mass. These results implicate heparanase in energy balance control via the central melanocortin system. Our data indicate that heparanase acts as a negative modulator of AgRP signaling at MC4R, through cleavage of heparan sulfate chains presumably linked to syndecan-3.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-175859 (URN)10.1371/journal.pone.0034313 (DOI)000303894900080 ()
Available from: 2012-06-13 Created: 2012-06-13 Last updated: 2017-12-07Bibliographically approved
Zhang, X., Wang, B., O'Callaghan, P., Hjertstrom, E., Jia, J., Gong, F., . . . Li, J.-P. (2012). Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-beta in murine brain. Acta Neuropathologica, 124(4), 465-478
Open this publication in new window or tab >>Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-beta in murine brain
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2012 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 124, no 4, p. 465-478Article in journal (Refereed) Published
Abstract [en]

Neuroinflammation is typically observed in neurodegenerative diseases such as Alzheimer's disease, as well as after traumatic injury and pathogen infection. Resident immune cells, microglia and astrocytes, are activated and joined by blood-borne monocytes that traverse the blood-brain barrier and convert into activated macrophages. The activated cells express various cytokines, chemokines and proteolytic enzymes. To study the role of heparan sulfate proteoglycans in neuroinflammation, we employed a transgenic mouse overexpressing heparanase, an endoglucuronidase that specifically degrades heparan sulfate side chains. Neuroinflammation was induced by systemic challenge with lipopolysaccharide, or by localized cerebral microinjection of aggregated amyloid-beta peptide, implicated in Alzheimer's disease. Lipopolysaccharide-treated control mice showed massive activation of resident microglia as well as recruitment of monocyte-derived macrophages into the brain parenchyma. Microinjection of aggregated amyloid-beta elicited a similar inflammatory response, albeit restricted to the injection site, which led to dispersion and clearance of the amyloid. In the heparanase-overexpressing mice, all aspects of immune cell recruitment and activation were significantly attenuated in both inflammation models, as was amyloid dispersion. Accordingly, an in vitro blood-brain barrier model constructed from heparanase-overexpressing cerebral vascular cells showed impaired transmigration of monocytes compared to a corresponding assembly of control cells. Our data indicate that intact heparan sulfate chains are required at multiple sites to mediate neuroinflammatory responses, and further point to heparanase as a modulator of this process, with potential implications for Alzheimer's disease.

Keywords
Neuroinflammation, Heparan sulfate, Heparanase, Amyloid-beta, Clearance, Alzheimer's disease
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-183208 (URN)10.1007/s00401-012-0997-1 (DOI)000308962300002 ()22692572 (PubMedID)
Available from: 2012-10-26 Created: 2012-10-23 Last updated: 2017-12-07
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