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Size-Selective Phagocytic Clearance of Fibrillar Α-Synuclein Through Size-Selective Phagocytic Clearance of Fibrillar α-Synuclein through Conformational Activation of Complement Receptor 4 This information is current as of September 25, 2021. Kristian Juul-Madsen, Per Qvist, Kirstine L. Bendtsen, Annette E. Langkilde, Bente Vestergaard, Kenneth A. Howard, Martxel Dehesa-Etxebeste, Søren R. Paludan, Gregers Rom Andersen, Poul Henning Jensen, Daniel E. Otzen, Marina Romero-Ramos and Thomas Vorup-Jensen Downloaded from J Immunol published online 22 January 2020 http://www.jimmunol.org/content/early/2020/01/21/jimmun ol.1900494 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2020/01/22/jimmunol.190049 Material 4.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published January 22, 2020, doi:10.4049/jimmunol.1900494 The Journal of Immunology Size-Selective Phagocytic Clearance of Fibrillar a-Synuclein through Conformational Activation of Complement Receptor 4 Kristian Juul-Madsen,*,† Per Qvist,†,‡,x Kirstine L. Bendtsen,{ Annette E. Langkilde,{ Bente Vestergaard,{ Kenneth A. Howard,‖ Martxel Dehesa-Etxebeste,#,** Søren R. Paludan,† Gregers Rom Andersen,†† Poul Henning Jensen,†,‡‡ Daniel E. Otzen,‖ Marina Romero-Ramos,†,‡‡,xx and Thomas Vorup-Jensen*,†,‖,xx Aggregation of a-synuclein (aSN) is an important histological feature of Parkinson disease. Recent studies showed that the release of misfolded aSN from human and rodent neurons is relevant to the progression and spread of aSN pathology. Little is known, however, about the mechanisms responsible for clearance of extracellular aSN. This study found that human complement a a receptor (CR) 4 selectively bound fibrillar SN, but not monomeric species. SN is an abundant protein in the CNS, which Downloaded from potentially could overwhelm clearance of cytotoxic aSN species. The selectivity of CR4 toward binding fibrillar aSN consequently adds an important aSN receptor function for maintenance of brain homeostasis. Based on the recently solved structures of aSN fibrils and the known ligand preference of CR4, we hypothesize that the parallel monomer stacking in fibrillar aSN 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 aSN by human monocytes. The induced change coupled concomitantly with a phagolysosome formation. Data mining of the brain transcriptome in Parkinson disease patients supported CR4 as an active SN http://www.jimmunol.org/ 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. The Journal of Immunology, 2020, 204: 000–000. arkinson disease (PD), Lewy body dementia, and multiple receptor-mediated endocytosis (1). Some study findings sug- system atrophy are among the most prevalent neurode- gested that this mechanism is a means of protective clearance P generative diseases. Aggregation of the cytosolic protein (5). However, the intercellular transfer can initiate an inflamma- a-synuclein (aSN) into cell body inclusions (i.e., Lewy bodies) tory response in microglia and nucleate further intracellular ag- (1), with aSN as the main component, is a shared histological gregation, which ultimately exacerbates neurodegeneration and by guest on September 25, 2021 hallmark of these diseases (2). Lewy bodies are terminal products promotes disease (1, 6). Consistent with this notion, genetic PD of the complex pathway of aSN aggregate formation; they consist risk variants are significantly enriched in gene sets functionally of fibrils of many thousands of aSN monomers. Many smaller linked to the regulation of leukocyte activity (7). Microglial cells types of aSN oligomers are also formed during aggregation. are the main resident myeloid leukocyte in the CNS. They are These oligomers may be the species responsible for cytotoxicity especially enriched in the substantia nigra, which shows the most due to their high mobility and ability to perturb the cell mem- prevalent neuronal death during PD (8). It is proposed that brane. Fibrils have been considered to be more innocuous, but microglial cells are aSN scavengers (9). Secreted aSN is cyto- study results reveal an important cell toxicity role for fibrils toxic to recipient neural cells in vitro (10) and in vitro–generated (3, 4). The aSN aggregates can be released to the extracellular oligomers of recombinant aSN are up to 17-fold more cytotoxic environment and then transfer from neuron to neuron through than monomers (11). aSN is one of the most abundant proteins in *Biophysical Immunology Laboratory, Aarhus University, DK-8000 Aarhus C, M.R.-R. K.L.B., A.E.L., and B.V. acknowledge funding from the Lundbeck Founda- Denmark; †Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, tion Initiative BRAINSTRUC (2015-2666). Denmark; ‡iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiat- x Address correspondence and reprint requests to Prof. Thomas Vorup-Jensen, Bio- ric Research, Aarhus University, DK-8000 Aarhus C, Denmark; iSEQ, Centre for physical Immunology Laboratory, Department of Biomedicine, Aarhus University, Integrative Sequencing, Department of Biomedicine, Aarhus University, DK-8000 { The Bartholin Building (Building 1240), Wilhelm Meyers Alle, DK-8000 Aarhus C, Aarhus C, Denmark; Department of Drug Design and Pharmacology, University of ‖ Denmark. E-mail address: [email protected] Copenhagen, DK-2100 Copenhagen Ø, Denmark; Interdisciplinary Nanoscience Center, Aarhus University, DK-8000 Aarhus C, Denmark; #Neuroscience Area, Bio- The online version of this article contains supplemental material. donostia Research Institute, 20014 Donostia, San Sebastian, Spain; **CIBERNED, Abbreviations used in this article: CR, complement receptor; DAMP, danger- Instituto de Salud Carlos III, 28029 Madrid, Spain; ††Department of Molecular Biol- associated molecular pattern; Gu·HCl, guanidine hydrochloride; I, inserted; a , ogy and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark; ‡‡DANDRITE– M a-chain of CR3; a I, a I domain; MIDAS, metal ion-dependent adhesion site; Danish Research Institute of Translational Neuroscience, Aarhus University, M M xx NTA, nanoparticle tracking analysis; PD, Parkinson disease; PFF, preformed DK-8000 Aarhus C, Denmark; and NEURODIN AU IDEAS Center, Department fibril; Q-dot, quantum dot; RNA-seq, RNA sequencing; RU, resonance unit; of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark aSN, a-synuclein; SPR, surface plasma resonance; tc, contact time; TEM, trans- ORCIDs: 0000-0002-5309-5221 (K.J.-M.); 0000-0002-0750-0089 (P.Q.); 0000- mission electron microscopy; ThT, thioflavin T; TPM, transcript per million; Wt, 0002-3976-8143 (K.L.B.); 0000-0003-2467-4205 (A.E.L.); 0000-0003-3230- wild-type; aX, a-chain of CR4; aXI, aX I domain. 9566 (M.D.-E.); 0000-0001-9180-4060 (S.R.P.); 0000-0001-6292-3319 (G.R.A.); 0000-0003-0970-578X (M.R.-R.); 0000-0002-4140-6563 (T.V.-J.). Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 Received for publication May 1, 2019. Accepted for publication December 18, 2019. This work was supported by an Aarhus University Research Foundation “NOVA” grant (AUFF-E-2015FLS-9-6) to T.V.-J. and K.J.-M. and an IDEAS Center grant to www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900494 2 a-SYNUCLEIN CLEARANCE BY COMPLEMENT RECEPTOR 4 the CNS; it accounts for 0.5–1% of all cytosolic brain protein (12). the MIDAS (32). The human aXI, especially, carries positive To limit aSN cytotoxicity during neural cell death, receptor- charges, which are involved in ligand recognition (33, 34), and mediated aSN clearance must bind aSN oligomers and fibrils almost no negative charge (Fig. 2C), which would further act to while avoiding saturation with the monomeric species. A study accommodate motifs of uninterrupted negative charge (29). The using a murine model found that predominantly aggregated aSN stretches of anionic charge, guided by the parallel organization of is an agonist of TLR-2 and stimulates microglial activation (13). the aSN monomers in the aggregates, suggest that CR4 is a strong A mouse model of multiple system atrophy revealed that TLR-4 receptor, especially for fibrillar aSN, but, to our knowledge, CR4 is associated with aSN clearance (14). It also associated with aSN has not been examined as a receptor for aSN. The roles of CR3 or activation of microglial cells by monomeric and fibrillar forms CR4 in aSN phagocytosis have also not been determined. Indi- (15). However, although TLRs are critical for the sensing of
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