MDM2-linked microglial dysfunction in obsessive-compulsive disorder

MDM2-linked microglial dysfunction in obsessive-compulsive disorder | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article MDM2-linked microglial dysfunction in obsessive-compulsive disorder Soyoung Sung, Junho Park, Chan Rim, Hui-Ju Kim, Sang-Hyuk Lee, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9325069/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Microglia, the resident immune cells of the central nervous system, are essential for immune surveillance and synaptic remodeling, and have been implicated in various neuropsychiatric disorders. However, their role in the pathophysiology of obsessive-compulsive disorder (OCD) remains unclear. Here we identify molecular and functional impairments in induced microglia-like cells (iMGs) derived from peripheral monocytes of OCD patients (n=23), compared with those from healthy controls (HC, n=24) and individuals with social anxiety disorder (SAD, n=16). Transcriptomic profiling revealed a selective reduction of Murine double minute 2 (MDM2) expression in OCD-iMGs, which correlated inversely with symptom severity measured by the dimensional obsessive-compulsive scale (DOCS) total score. Functional knockdown (KD) of MDM2 in primary microglia impaired synaptosome phagocytosis and dampened inflammatory responses to lipopolysaccharide (LPS). In addition, MDM2 KD microglia showed reduction of furin and mature BDNF (brain-derived neurotrophic factor) expression. Drug screening using Connectivity Map identified bortezomib (BTZ) as a candidate compound capable of reversing the OCD-associated microglial features. BTZ restored MDM2 expression and mBDNF, leading to restoration of phagocytic function in MDM2 KD microglia and OCD-iMGs. Finally, BTZ attenuatedrepetitive behaviors in a serotonergic mouse model, suggesting that the MDM2–BDNF pathway may represent a candidate target in OCD. MDM2 Microglia Obsessive-compulsive disorder Bortezomib BDNF Full Text Additional Declarations No competing interests reported. Supplementary Files SupportinginformationJNI.docx sTable1.docx sTable2primer.docx sTable3.xlsx sTable4.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 06 May, 2026 Reviewers agreed at journal 01 May, 2026 Reviewers agreed at journal 13 Apr, 2026 Reviewers invited by journal 08 Apr, 2026 Editor assigned by journal 08 Apr, 2026 Submission checks completed at journal 08 Apr, 2026 First submitted to journal 05 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9325069","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":622064446,"identity":"abf76f81-4022-48ee-931f-e66cef160fa5","order_by":0,"name":"Soyoung Sung","email":"","orcid":"","institution":"CHA University","correspondingAuthor":false,"prefix":"","firstName":"Soyoung","middleName":"","lastName":"Sung","suffix":""},{"id":622064447,"identity":"a7f2935f-a0f3-40ef-8535-34270f53b83c","order_by":1,"name":"Junho Park","email":"","orcid":"","institution":"CHA 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