Daniel Otzen

Size-Selective Phagocytic Clearance of Fibrillar α-Synuclein through Conformational Activation of Complement Receptor 4

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Size-Selective Phagocytic Clearance of Fibrillar α-Synuclein through Conformational Activation of Complement Receptor 4. / Juul-Madsen, Kristian; Qvist, Per; Bendtsen, Kirstine L et al.

In: Journal of Immunology, Vol. 204, No. 5, 2020, p. 1345-1361.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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Juul-Madsen K, Qvist P, Bendtsen KL, Langkilde AE, Vestergaard B, Howard K et al. Size-Selective Phagocytic Clearance of Fibrillar α-Synuclein through Conformational Activation of Complement Receptor 4. Journal of Immunology. 2020;204(5):1345-1361. doi: 10.4049/jimmunol.1900494

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@article{52a3e09cf194471f852260b7078cce62,
title = "Size-Selective Phagocytic Clearance of Fibrillar α-Synuclein through Conformational Activation of Complement Receptor 4",
abstract = "Aggregation of α-synuclein (αSN) is an important histological feature of Parkinson disease. Recent studies showed that the release of misfolded αSN from human and rodent neurons is relevant to the progression and spread of αSN pathology. Little is known, however, about the mechanisms responsible for clearance of extracellular αSN. This study found that human complement receptor (CR) 4 selectively bound fibrillar αSN, but not monomeric species. αSN is an abundant protein in the CNS, which potentially could overwhelm clearance of cytotoxic αSN species. The selectivity of CR4 toward binding fibrillar αSN consequently adds an important αSN receptor function for maintenance of brain homeostasis. Based on the recently solved structures of αSN fibrils and the known ligand preference of CR4, we hypothesize that the parallel monomer stacking in fibrillar αSN creates a known danger-associated molecular pattern of stretches of anionic side chains strongly bound by CR4. Conformational change in the receptor regulated tightly clearance of fibrillar αSN by human monocytes. The induced change coupled concomitantly with phagolysosome formation. Data mining of the brain transcriptome in Parkinson disease patients supported CR4 as an active αSN clearance mechanism in this disease. Our results associate an important part of the innate immune system, namely complement receptors, with the central molecular mechanisms of CNS protein aggregation in neurodegenerative disorders.",
author = "Kristian Juul-Madsen and Per Qvist and Bendtsen, {Kirstine L} and Langkilde, {Annette E} and Bente Vestergaard and Ken Howard and Martxel Dehesa-Etxebeste and Paludan, {S{\o}ren R} and Andersen, {Gregers Rom} and Jensen, {Poul Henning} and Otzen, {Daniel E} and Marina Romero-Ramos and Thomas Vorup-Jensen",
note = "Copyright {\textcopyright} 2020 by The American Association of Immunologists, Inc.",
year = "2020",
doi = "10.4049/jimmunol.1900494",
language = "English",
volume = "204",
pages = "1345--1361",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "5",

}

RIS

TY - JOUR

T1 - Size-Selective Phagocytic Clearance of Fibrillar α-Synuclein through Conformational Activation of Complement Receptor 4

AU - Juul-Madsen, Kristian

AU - Qvist, Per

AU - Bendtsen, Kirstine L

AU - Langkilde, Annette E

AU - Vestergaard, Bente

AU - Howard, Ken

AU - Dehesa-Etxebeste, Martxel

AU - Paludan, Søren R

AU - Andersen, Gregers Rom

AU - Jensen, Poul Henning

AU - Otzen, Daniel E

AU - Romero-Ramos, Marina

AU - Vorup-Jensen, Thomas

N1 - Copyright © 2020 by The American Association of Immunologists, Inc.

PY - 2020

Y1 - 2020

N2 - Aggregation of α-synuclein (αSN) is an important histological feature of Parkinson disease. Recent studies showed that the release of misfolded αSN from human and rodent neurons is relevant to the progression and spread of αSN pathology. Little is known, however, about the mechanisms responsible for clearance of extracellular αSN. This study found that human complement receptor (CR) 4 selectively bound fibrillar αSN, but not monomeric species. αSN is an abundant protein in the CNS, which potentially could overwhelm clearance of cytotoxic αSN species. The selectivity of CR4 toward binding fibrillar αSN consequently adds an important αSN receptor function for maintenance of brain homeostasis. Based on the recently solved structures of αSN fibrils and the known ligand preference of CR4, we hypothesize that the parallel monomer stacking in fibrillar αSN creates a known danger-associated molecular pattern of stretches of anionic side chains strongly bound by CR4. Conformational change in the receptor regulated tightly clearance of fibrillar αSN by human monocytes. The induced change coupled concomitantly with phagolysosome formation. Data mining of the brain transcriptome in Parkinson disease patients supported CR4 as an active αSN clearance mechanism in this disease. Our results associate an important part of the innate immune system, namely complement receptors, with the central molecular mechanisms of CNS protein aggregation in neurodegenerative disorders.

AB - Aggregation of α-synuclein (αSN) is an important histological feature of Parkinson disease. Recent studies showed that the release of misfolded αSN from human and rodent neurons is relevant to the progression and spread of αSN pathology. Little is known, however, about the mechanisms responsible for clearance of extracellular αSN. This study found that human complement receptor (CR) 4 selectively bound fibrillar αSN, but not monomeric species. αSN is an abundant protein in the CNS, which potentially could overwhelm clearance of cytotoxic αSN species. The selectivity of CR4 toward binding fibrillar αSN consequently adds an important αSN receptor function for maintenance of brain homeostasis. Based on the recently solved structures of αSN fibrils and the known ligand preference of CR4, we hypothesize that the parallel monomer stacking in fibrillar αSN creates a known danger-associated molecular pattern of stretches of anionic side chains strongly bound by CR4. Conformational change in the receptor regulated tightly clearance of fibrillar αSN by human monocytes. The induced change coupled concomitantly with phagolysosome formation. Data mining of the brain transcriptome in Parkinson disease patients supported CR4 as an active αSN clearance mechanism in this disease. Our results associate an important part of the innate immune system, namely complement receptors, with the central molecular mechanisms of CNS protein aggregation in neurodegenerative disorders.

U2 - 10.4049/jimmunol.1900494

DO - 10.4049/jimmunol.1900494

M3 - Journal article

C2 - 31969389

VL - 204

SP - 1345

EP - 1361

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 5

ER -