{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:27:39Z","timestamp":1792016859289,"version":"4.4.0"},"reference-count":79,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T00:00:00Z","timestamp":1693958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010785","name":"Canada First Research Excellence Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010785","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008582","name":"McGill University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008582","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000156","name":"Fonds de recherche du Qu\u00e9bec\u2014Sant\u00e9","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000156","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CIHR Foundation"},{"name":"Fonds d\u2019Acc\u00e9leration des Collaborations en Sant\u00e9"},{"name":"FRQS Chercheurs-boursiers award"},{"name":"Parkinson Quebec"},{"name":"William Dawson Scholar"},{"name":"CQDM\u2019s Health Collaborations Accelerator Fund program"},{"name":"Quantum Leaps program"},{"name":"Sebastian and Ghislaine van Berkom Foundation"},{"name":"Alain and Sandra Bouchard Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mer tyrosine kinase (MerTK) is a receptor tyrosine kinase that mediates non-inflammatory, homeostatic phagocytosis of diverse types of cellular debris. Highly expressed on the surface of microglial cells, MerTK is of importance in brain development, homeostasis, plasticity and disease. Yet, involvement of this receptor in the clearance of protein aggregates that accumulate with ageing and in neurodegenerative diseases has yet to be defined. The current study explored the function of MerTK in the microglial uptake of alpha-synuclein fibrils which play a causative role in the pathobiology of synucleinopathies.<\/jats:p>\n                  <jats:p>Using human primary and induced pluripotent stem cell-derived microglia, the MerTK-dependence of alpha-synuclein fibril internalization was investigated in vitro. Relevance of this pathway in synucleinopathies was assessed through burden analysis of MERTK variants and analysis of MerTK expression in patient-derived cells and tissues.<\/jats:p>\n                  <jats:p>Pharmacological inhibition of MerTK and siRNA-mediated MERTK knockdown both caused a decreased rate of alpha-synuclein fibril internalization by human microglia. Consistent with the non-inflammatory nature of MerTK-mediated phagocytosis, alpha-synuclein fibril internalization was not observed to induce secretion of pro-inflammatory cytokines such as IL-6 or TNF, and downmodulated IL-1\u03b2 secretion from microglia. Burden analysis in two independent patient cohorts revealed a significant association between rare functionally deleterious MERTK variants and Parkinson\u2019s disease in one of the cohorts (P = 0.002). Despite a small upregulation in MERTK mRNA expression in nigral microglia from Parkinson\u2019s disease\/Lewy body dementia patients compared to those from non-neurological control donors in a single-nuclei RNA-sequencing dataset (P = 5.08 \u00d7 10\u221221), no significant upregulation in MerTK protein expression was observed in human cortex and substantia nigra lysates from Lewy body dementia patients compared to controls.<\/jats:p>\n                  <jats:p>Taken together, our findings define a novel role for MerTK in mediating the uptake of alpha-synuclein fibrils by human microglia, with possible involvement in limiting alpha-synuclein spread in synucleinopathies such as Parkinson\u2019s disease. Upregulation of this pathway in synucleinopathies could have therapeutic values in enhancing alpha-synuclein fibril clearance in the brain.<\/jats:p>","DOI":"10.1093\/brain\/awad298","type":"journal-article","created":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T05:29:56Z","timestamp":1693978196000},"page":"427-443","source":"Crossref","is-referenced-by-count":43,"title":["MerTK is a mediator of alpha-synuclein fibril uptake by human microglia"],"prefix":"10.1093","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1285-6087","authenticated-orcid":false,"given":"Marie-France","family":"Dorion","sequence":"first","affiliation":[{"name":"Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Neuroimmunology Unit, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moein","family":"Yaqubi","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin","family":"Senkevich","sequence":"additional","affiliation":[{"name":"McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Human Genetics, McGill University , Montreal H3A 0C7 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas W","family":"Kieran","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol X Q","family":"Chen","sequence":"additional","affiliation":[{"name":"Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Luo","sequence":"additional","affiliation":[{"name":"Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Wallis","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute, University College London , London WC1E 6BT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Shlaifer","sequence":"additional","affiliation":[{"name":"Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery A","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy W R","family":"Dudley","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Division of Neurosurgery, Montreal Children's Hospital, McGill University Health Centers , Montreal H4A 3J1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian A","family":"Glass","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Washington , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Birth Defects Research Laboratory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo Anne","family":"Stratton","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5520-6239","authenticated-orcid":false,"given":"Edward A","family":"Fon","sequence":"additional","affiliation":[{"name":"Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Bartels","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute, University College London , London WC1E 6BT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack P","family":"Antel","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0332-234X","authenticated-orcid":false,"given":"Ziv","family":"Gan-or","sequence":"additional","affiliation":[{"name":"McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Human Genetics, McGill University , Montreal H3A 0C7 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3942-1956","authenticated-orcid":false,"given":"Thomas M","family":"Durcan","sequence":"additional","affiliation":[{"name":"Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9496-2216","authenticated-orcid":false,"given":"Luke M","family":"Healy","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill 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