{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T21:01:54Z","timestamp":1793826114225,"version":"4.6.1"},"reference-count":51,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"772","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,11,6]]},"abstract":"<jats:p>\n                    Age is the greatest risk factor for many neurodegenerative diseases, yet immune system aging, a contributor to neurodegeneration, is understudied. Genetic variation in the\n                    <jats:italic>LRRK2<\/jats:italic>\n                    gene affects risk for both familial and sporadic Parkinson\u2019s disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein is implicated in peripheral immune cell signaling, but the effects of an aging immune system on LRRK2 function remain unclear. We analyzed peritoneal macrophages from\n                    <jats:italic>R1441C-Lrrk2<\/jats:italic>\n                    knock-in mice and observed a biphasic, age-dependent effect of the\n                    <jats:italic>R1441C-Lrrk2<\/jats:italic>\n                    mutation on peritoneal macrophage function. We report increases in antigen presentation, anti-inflammatory cytokine production, lysosomal activity, and pathogen uptake in peritoneal macrophages from young (2- to 3-month-old) female\n                    <jats:italic>R1441C-Lrrk2<\/jats:italic>\n                    mice. Conversely, macrophages from aged (18- to 21-month-old) female\n                    <jats:italic>R1441C-Lrrk2<\/jats:italic>\n                    mice exhibited decreased antigen presentation after inflammatory insult, decreased lysosomal function, and pathogen uptake, with a concomitant increase in DNA fragmentation in the presence of pathogens. This immune cell exhaustion phenotype was not observed in male\n                    <jats:italic>R1441C-Lrrk2<\/jats:italic>\n                    mice and was driven by increased LRRK2 protein kinase activity. This phenotype was also observed in human peripheral myeloid cells, with monocyte-derived macrophages from patients with PD who had either the\n                    <jats:italic>R1441C-<\/jats:italic>\n                    or\n                    <jats:italic>Y1699C-LRRK2<\/jats:italic>\n                    mutation exhibiting decreased pathogen uptake and increased PDL1 expression, consistent with immune cell exhaustion. Our findings that LRRK2 mutations conferred an immunological advantage at a young age but could predispose the carrier to age-acquired immune cell exhaustion have implications for the therapeutic development of LRRK2 inhibitors.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adl1535","type":"journal-article","created":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T13:58:18Z","timestamp":1730901498000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":19,"title":["The\n                    <i>R1441C-Lrrk2<\/i>\n                    mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner in mice"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0947-4459","authenticated-orcid":true,"given":"Rebecca L.","family":"Wallings","sequence":"first","affiliation":[{"name":"Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA."},{"name":"Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA."},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9952-8678","authenticated-orcid":true,"given":"Karen","family":"McFarland","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA."},{"name":"Department of Neurology and Fixel Institute for Neurological Diseases, University of Florida Health, Gainesville, FL, USA."},{"name":"Department of Pharmacology, Emory University, Atlanta, GA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8284-6178","authenticated-orcid":true,"given":"Hannah A.","family":"Staley","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA."},{"name":"Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6649-0988","authenticated-orcid":true,"given":"Noelle","family":"Neighbarger","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA."},{"name":"Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6021-3069","authenticated-orcid":true,"given":"Susen","family":"Schaake","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of L\u00fcbeck, L\u00fcbeck, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Br\u00fcggemann","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of L\u00fcbeck, L\u00fcbeck, Germany."},{"name":"Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Zittel","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7335-8888","authenticated-orcid":true,"given":"Tatiana","family":"Usnich","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of L\u00fcbeck, L\u00fcbeck, Germany."},{"name":"Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2102-3431","authenticated-orcid":true,"given":"Christine","family":"Klein","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA."},{"name":"Institute of Neurogenetics, University of L\u00fcbeck, L\u00fcbeck, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3218-7116","authenticated-orcid":true,"given":"Esther M.","family":"Sammler","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA."},{"name":"MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK."},{"name":"Department of Neurology, School of Medicine, Ninewells Hospital, Ninewells Drive, Dundee DD1 9SY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mal\u00fa G\u00e1mez","family":"Tansey","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA."},{"name":"Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA."},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA."},{"name":"Department of 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