{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:04:26Z","timestamp":1782281066543,"version":"3.54.5"},"posted":{"date-parts":[[2026,1,12]]},"group-title":"Neuroscience","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The genomic locus that encodes the Leucine-rich repeat kinase 2 (LRRK2) gene is highly pleiotropic, being associated with both Parkinson\u2019s disease (PD) and Crohn\u2019s disease (CD). Coding variants associated with risk of PD and CD act as gain of function kinase mutations increasing phosphorylation of RAB substrates, and non-coding variants in the promoter region of LRRK2 increase expression of the gene, notably in immune cells. If regulation of LRRK2 expression is a causal contributor to age-related diseases, it is important to understand the mechanism(s) by which LRRK2 is regulated, particularly in the context of inflammation. Here, we show that interferon-\u0263 exposure induces robust LRRK2 activation in human iPSC-derived microglia through signaling of the Janus-activated Kinase complex to phosphorylate STAT1, which then binds to the LRRK2 promoter and is associated with remodeling of chromatin structure in this genomic locus. Additional regulatory mechanisms include the stress-induced transcription factor and long non-coding RNA encoded at the same locus, resulting in increased LRRK2 mRNA levels. We also show evidence of the same effect in acutely cultured human brain slices. While we were unable to demonstrate any induction of Lrrk2 mRNA in the mouse brain, the introduction of a human bacterial artificial chromosome transgene into the mouse genome recapitulated sensitivity to interferon-\u0263 in microglia. A comparative genomic analysis across mammals suggests that these species differences are driven by regulatory regions upstream of LRRK2 that are specific to anthropoid primates. These results demonstrate that there are differences between species in how genes associated with human diseases are regulated and provide important information that should be incorporated in disease modeling.<\/jats:p>","DOI":"10.64898\/2026.01.11.698894","type":"posted-content","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T03:00:10Z","timestamp":1768273210000},"source":"Crossref","is-referenced-by-count":0,"title":["Inflammatory signaling differentially changes chromatin accessibility and gene expression of the PD- associated kinase LRRK2 between human and mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6400-1684","authenticated-orcid":false,"given":"Alexandra","family":"Beilina","sequence":"first","affiliation":[{"name":"Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hyeon","family":"Park","sequence":"additional","affiliation":[{"name":"Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8399-4009","authenticated-orcid":false,"given":"Natalie","family":"Landeck","sequence":"additional","affiliation":[{"name":"Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4709-7423","authenticated-orcid":false,"given":"Ruth","family":"Chia","sequence":"additional","affiliation":[{"name":"Neuromuscular Disease Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhui","family":"Ding","sequence":"additional","affiliation":[{"name":"Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7563-9365","authenticated-orcid":false,"given":"Xylena","family":"Reed","sequence":"additional","affiliation":[{"name":"Single Cell Expert group, Center for Alzheimer\u2019s and Related Dementia, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Bailey","sequence":"additional","affiliation":[{"name":"Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on 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J.","family":"Acri","sequence":"additional","affiliation":[{"name":"Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4762-132X","authenticated-orcid":false,"given":"Janet","family":"Brooks","sequence":"additional","affiliation":[{"name":"Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Mann","sequence":"additional","affiliation":[{"name":"Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 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