Glial multicellular programs reveal distinct patient stratification in Parkinson's disease

Glial multicellular programs reveal distinct patient stratification in Parkinson's disease | 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 Article Glial multicellular programs reveal distinct patient stratification in Parkinson's disease Ana Munoz-Manchado, Juan M. Barba Reyes, Sergio Marco Salas, Gabriel González Ulloa, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9520754/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by nigrostriatal degeneration. While the role of glial cells in PD is increasingly recognized, the coordinated multicellular responses driving PD within the dorsal striatum remain poorly understood. By integrating single-nucleus RNA sequencing of 56 donors with targeted spatial transcriptomics, we disentangle regional from PD-related molecular programs across astrocytes, microglia and oligodendroglia. We identify PD-associated glial subpopulations organized into two distinct multicellular programs: one inflammatory and one UPR-associated, where each patient is dominated by one of these programs. Notably, these programs partition the molecular changes typically associated with PD into two specific, non-overlapping signatures. Multi-region analysis revealed these signatures are globally enriched across the sampled areas and Lewy body disease stages, from brainstem-predominant to neocortical, demonstrating that PD is characterized by mutually exclusive, brain-wide glial multicellular states. Our findings redefine glial alterations in PD as systemic and multicellular, providing a framework for patient stratification and the development of targeted, state-specific therapeutic interventions. Biological sciences/Neuroscience/Genetics of the nervous system Health sciences/Diseases/Neurological disorders Full Text Additional Declarations Yes there is potential Competing Interest. B.T.H owns stock in Novartis; he serves on the SAB of Dewpoint and has an option for stock. He serves on a scientific advisory board or is a consultant for AbbVie,Alexion, Ambagon, Aprinoia Therapeutics, Arvinas, Avrobio, AstraZenica, Biogen, Bioinsights, BMS, Cure Alz Fund, Cell Signaling, Dewpoint, Latus, Merck, Novartis, Pfizer, Sanofi, Sofinnova, Takeda, TD Cowen, Vigil, Violet, Voyager, WaveBreak. His laboratory is supported by research grants from the National Institutes of Health, Cure Alzheimer’s Fund, Tau Consortium, and the JPB Foundation – and a sponsored research agreement from Abbvie and Sanofi. He has a collaborative project with Biogen. A.S.-P. is supported by research grants from the National Institutes of Health and the Alzheimer’s Association, has received research funds from Abbvie, inc., and has a Material Transfer Agreement with Ionis Pharmaceuticals, Inc. S.M.S. is a co-founder of Spatialist AB, a consulting company focused on spatial transcriptomics data analysis. F.J.T. consults for Immunai, CytoReason, BioTuring, Genbio and Valinor Industries, and has ownership interest in RN.AI Therapeutics, Dermagnostix, and Cellarity. R.K.R. advised iuvando GmbH and consults for RN.AI Therapeutics. The rest of the authors declare no competing interests. Supplementary Files SupplementaryTablesLegend.pdf Supplementary Tables SupplementaryFigures.pdf Supplementary Figures UnifiedExtendedDataTables.xlsx Unified Extended Data Tables Cite Share Download PDF Status: Under Review Version 1 posted 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-9520754","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":631723370,"identity":"86f5af9a-8a88-4f7b-b9ec-3bc1acf4920c","order_by":0,"name":"Ana Munoz-Manchado","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAs0lEQVRIiWNgGAWjYFAD9gaStfAcIFmLRAKRCvlnNz9gutl2R05+5hvDDz8YbOwJm33nmAFzbtszY8bZOcaSPQxpiQ0E9dxIAGk5nNgsnWPGwMNwmLDz5G+kfwBraZM8Y8b4h+E/YYcZ3MiB2NIjwWPGzMNwgJGgwwxv5BQczjl32FiCJ61YWsYgmbBf5G6kb3ycU3ZYTr798MaPbyrsCDsMBA4guZMoDaNgFIyCUTAKCAEAlB03xcmPwosAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-1121-6072","institution":"University of Cadiz","correspondingAuthor":true,"prefix":"","firstName":"Ana","middleName":"","lastName":"Munoz-Manchado","suffix":""},{"id":631723371,"identity":"b9401519-290e-464c-9d92-229ccd974af8","order_by":1,"name":"Juan M. 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He serves on a scientific advisory board or is a consultant for AbbVie,Alexion, Ambagon, Aprinoia Therapeutics, Arvinas, Avrobio, AstraZenica, Biogen, Bioinsights, BMS, Cure Alz Fund, Cell Signaling, Dewpoint, Latus, Merck, Novartis, Pfizer, Sanofi, Sofinnova, Takeda, TD Cowen, Vigil, Violet, Voyager, WaveBreak. His laboratory is supported by research grants from the National Institutes of Health, Cure Alzheimer’s Fund, Tau Consortium, and the JPB Foundation – and a sponsored research agreement from Abbvie and Sanofi. 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R.K.R. advised iuvando GmbH and consults for RN.AI Therapeutics.\r\nThe rest of the authors declare no competing interests.","formattedTitle":"Glial multicellular programs reveal distinct patient stratification in Parkinson's disease","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9520754/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9520754/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Parkinson’s disease (PD) is a neurodegenerative disorder characterized by nigrostriatal degeneration. While the role of glial cells in PD is increasingly recognized, the coordinated multicellular responses driving PD within the dorsal striatum remain poorly understood. By integrating single-nucleus RNA sequencing of 56 donors with targeted spatial transcriptomics, we disentangle regional from PD-related molecular programs across astrocytes, microglia and oligodendroglia. We identify PD-associated glial subpopulations organized into two distinct multicellular programs: one inflammatory and one UPR-associated, where each patient is dominated by one of these programs. Notably, these programs partition the molecular changes typically associated with PD into two specific, non-overlapping signatures. Multi-region analysis revealed these signatures are globally enriched across the sampled areas and Lewy body disease stages, from brainstem-predominant to neocortical, demonstrating that PD is characterized by mutually exclusive, brain-wide glial multicellular states. Our findings redefine glial alterations in PD as systemic and multicellular, providing a framework for patient stratification and the development of targeted, state-specific therapeutic interventions.","manuscriptTitle":"Glial multicellular programs reveal distinct patient stratification in Parkinson's disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-30 04:37:38","doi":"10.21203/rs.3.rs-9520754/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-neuroscience","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"neuro","sideBox":"Learn more about [Nature Neuroscience](http://www.nature.com/neuro/)","snPcode":"","submissionUrl":"","title":"Nature Neuroscience","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"35d354cf-237e-4887-94d9-7d43e107b63d","owner":[],"postedDate":"April 30th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-07T21:05:20+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-06T07:32:06+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-30T06:40:38+00:00","index":1,"fulltext":"This content is not available."}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":67240899,"name":"Biological sciences/Neuroscience/Genetics of the nervous system"},{"id":67240900,"name":"Health sciences/Diseases/Neurological disorders"}],"tags":[],"updatedAt":"2026-04-30T04:37:38+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-30 04:37:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9520754","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9520754","identity":"rs-9520754","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}