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Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes

dc.contributor.authorScheiblich, Hannah
dc.contributor.authorDansokho, Cira
dc.contributor.authorMercan, Dilek
dc.contributor.authorSchmidt, Susanne V.
dc.contributor.authorBousset, Luc
dc.contributor.authorWischhof, Lena
dc.contributor.authorEikens, Frederik
dc.contributor.authorOdainic, Alexandru
dc.contributor.authorSpitzer, Jasper
dc.contributor.authorGriep, Angelika
dc.contributor.authorSchwartz, Stephanie
dc.contributor.authorBano, Daniele
dc.contributor.authorLatz, Eicke
dc.contributor.authorMelki, Ronald
dc.contributor.authorHeneka, Michael T.
dc.date2022-08-11T08:10:06.000
dc.date.accessioned2022-08-23T16:55:18Z
dc.date.available2022-08-23T16:55:18Z
dc.date.issued2021-09-22
dc.date.submitted2022-05-10
dc.identifier.citation<p>Scheiblich H, Dansokho C, Mercan D, Schmidt SV, Bousset L, Wischhof L, Eikens F, Odainic A, Spitzer J, Griep A, Schwartz S, Bano D, Latz E, Melki R, Heneka MT. Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes. Cell. 2021 Sep 30;184(20):5089-5106.e21. doi: 10.1016/j.cell.2021.09.007. Epub 2021 Sep 22. PMID: 34555357; PMCID: PMC8527836. <a href="https://doi.org/10.1016/j.cell.2021.09.007">Link to article on publisher's site</a></p>
dc.identifier.issn0092-8674 (Linking)
dc.identifier.doi10.1016/j.cell.2021.09.007
dc.identifier.pmid34555357
dc.identifier.urihttp://hdl.handle.net/20.500.14038/42687
dc.description.abstractMicroglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of inflammatory pathways. Here, we studied how microglia handle and cope with alpha-synuclein (alpha-syn) fibrils and their clearance. We found that microglia exposed to alpha-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer alpha-syn from overloaded microglia to neighboring naive microglia where the alpha-syn cargo got rapidly and effectively degraded. Lowering the alpha-syn burden attenuated the inflammatory profile of microglia and improved their survival. This degradation strategy was compromised in cells carrying the LRRK2 G2019S mutation. We confirmed the intercellular transfer of alpha-syn assemblies in microglia using organotypic slice cultures, 2-photon microscopy, and neuropathology of patients. Together, these data identify a mechanism by which microglia create an "on-demand" functional network in order to improve pathogenic alpha-syn clearance.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=34555357&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectLRRK2
dc.subjectalpha-synuclein
dc.subjectcell-to-cell transfer
dc.subjectclearance
dc.subjectdegradation
dc.subjectmicroglia
dc.subjectsynucleinopathies
dc.subjecttunneling nanotubes
dc.subjectCell Biology
dc.subjectImmunology and Infectious Disease
dc.titleMicroglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes
dc.typeJournal Article
dc.source.journaltitleCell
dc.source.volume184
dc.source.issue20
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5966&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4931
dc.identifier.contextkey29108674
refterms.dateFOA2022-08-23T16:55:18Z
html.description.abstract<p>Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of inflammatory pathways. Here, we studied how microglia handle and cope with alpha-synuclein (alpha-syn) fibrils and their clearance. We found that microglia exposed to alpha-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer alpha-syn from overloaded microglia to neighboring naive microglia where the alpha-syn cargo got rapidly and effectively degraded. Lowering the alpha-syn burden attenuated the inflammatory profile of microglia and improved their survival. This degradation strategy was compromised in cells carrying the LRRK2 G2019S mutation. We confirmed the intercellular transfer of alpha-syn assemblies in microglia using organotypic slice cultures, 2-photon microscopy, and neuropathology of patients. Together, these data identify a mechanism by which microglia create an "on-demand" functional network in order to improve pathogenic alpha-syn clearance.</p>
dc.identifier.submissionpathoapubs/4931
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.source.pages5089-5106.e21


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Copyright 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Except where otherwise noted, this item's license is described as Copyright 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).