Decoding the multiregional atlas of Parkinson's disease at single-cell resolution

Decoding the multiregional atlas of Parkinson's disease at single-cell resolution | 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 Decoding the multiregional atlas of Parkinson's disease at single-cell resolution Juan Andrés Tejedor-Serrano, Ángeles Arzalluz-Luque, Sonia Tarazona, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9220144/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Characterizing the multiregional cellular landscape of Parkinson's disease (PD) is essential for understanding its broad impact beyond the midbrain. To advance that goal, we analyzed single-nucleus RNA sequencing data from over 2.2 million nuclei across five brain regions from 93 donors. Compositional analysis identified region-specific alterations, including a reduction in layer 2/3 excitatory neurons in the primary motor cortex and an expansion of specific astrocyte, microglial and oligodendrocyte precursor subtypes in the dorsal motor nucleus of the vagus (DMNX). Differential expression analysis revealed that while most transcriptional changes are cell-type-specific, a core set of markers including BNIP3L, WSB1 and the non-coding RNA LINC00862 are ubiquitously dysregulated across lineages. Furthermore, glial and vascular populations in the DMNX exhibit convergent transcriptional profiles characterized by mitochondrial dysfunction, neuroinflammation and extracellular matrix remodeling. These results provide a high-resolution characterization of the molecular and cellular changes in PD, demonstrating that disease-associated alterations are highly dependent on the intersection of cell identity and anatomical location. Computational Neuroscience Parkinson's disease snRNA-Seq brain atlas computational neuroscience Full Text Additional Declarations The authors declare no competing interests. This study is based exclusively on previously collected and de-identified human data obtained through the Accelerating Medicines Partnership Parkinson’s Disease (AMP-PD) consortium. The data used in this work were generated from samples collected by four independent biobanks under their respective institutional review board (IRB) or ethics committee approvals, with informed consent obtained from all participants at the time of sample collection.We did not generate primary data, did not have access to identifiable participant information, and performed only secondary analyses of existing, de-identified datasets made available by AMP-PD in accordance with its data access policies. Therefore, we consider than no additional IRB or ethics committee approval was required for this secondary data analysis. Cite Share Download PDF Status: Posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-9220144","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":611844670,"identity":"27d0a250-06c6-4239-aa41-76deb956742c","order_by":0,"name":"Juan Andrés Tejedor-Serrano","email":"","orcid":"https://orcid.org/0009-0002-9722-7545","institution":"Universitat Politècnica de València","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"Andrés","lastName":"Tejedor-Serrano","suffix":""},{"id":611844674,"identity":"e7c6bf37-7d9a-4559-900e-ca5147a5ff89","order_by":1,"name":"Ángeles Arzalluz-Luque","email":"","orcid":"https://orcid.org/0000-0002-2959-0134","institution":"Spanish National Research Council","correspondingAuthor":false,"prefix":"","firstName":"Ángeles","middleName":"","lastName":"Arzalluz-Luque","suffix":""},{"id":611844675,"identity":"62ac9256-f86e-448b-9ea9-e25438a60dc3","order_by":2,"name":"Sonia Tarazona","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzUlEQVRIiWNgGAWjYBADOQZm4hVDlBqTriWxgWgN8u39Bz/8qNmW3s/OfICZd8dhBn7+A/i1GJw5zCzZc+x27sxmtgRm3jOHGSRnJBDQIpHMIM3Adjt3w2EeA2betjQGgxuEHDYjmfk3w7/b6fYwLfbnCTiM4UYymzRj2+0EA2awFhsGAwZCDjtz2Myyt++24YzDbAkH556x4ZG4QUCLfHvj4xs/vt2W5+8/fPDB2x0Scvz9hByGDA4wNjDwkKAeBIBaRsEoGAWjYBRgAAAAjz3gxcweNAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-5346-1407","institution":"Universitat Politècnica de València","correspondingAuthor":true,"prefix":"","firstName":"Sonia","middleName":"","lastName":"Tarazona","suffix":""},{"id":611844676,"identity":"d71d1429-08eb-4aa8-89cc-2c3ca1a79b9d","order_by":3,"name":"Jordi Martorell-Marugán","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIie2RsWrDMBCGzwjk5cCrSiB+BRlDaqhLXkXB4E4FjxkDgWRR6apCIW+RtQGDM3Z10dKQFwh0CTRDpTSEDnLasYO+4eAQH/f/CMDj+YcEEwAmzmuV9cMpAAH+F4XawVmK9S+KhcEPZSRXVrkAmT9s2ndYxteLabPbcXYnw3DzUVU5RNHKHUyu00yATp4bWjwpzu4lwbSneAlXSrgVVVLTRQeKYkrQKC8EoYe8Bt521D8pw6NyMMGQhNtPqwxfO4KdlNFRMfUFEhh8X4GOYLIhmeC6ULQsAslZYroMbkwXZK1bSeaz4G0/1reK1DXsx3mM0Xqrq0Pejx7dwZKJna6PQ3d5gLjrwePxeDxnvgCink5mJrBXvgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-5186-0735","institution":"Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO)","correspondingAuthor":true,"prefix":"","firstName":"Jordi","middleName":"","lastName":"Martorell-Marugán","suffix":""}],"badges":[],"createdAt":"2026-03-25 08:14:45","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9220144/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9220144/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106094015,"identity":"7d8415ac-8cc2-4917-9902-0c2f689b563e","added_by":"auto","created_at":"2026-04-03 11:40:42","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8169151,"visible":true,"origin":"","legend":"","description":"","filename":"TejedorSerranopreprint.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9220144/v1_covered_a0958e6d-81e3-413e-a98f-f744efe615b2.pdf"}],"financialInterests":"\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003eThis study is based exclusively on previously collected and de-identified human data obtained through the Accelerating Medicines Partnership Parkinson’s Disease (AMP-PD) consortium. The data used in this work were generated from samples collected by four independent biobanks under their respective institutional review board (IRB) or ethics committee approvals, with informed consent obtained from all participants at the time of sample collection.We did not generate primary data, did not have access to identifiable participant information, and performed only secondary analyses of existing, de-identified datasets made available by AMP-PD in accordance with its data access policies. Therefore, we consider than no additional IRB or ethics committee approval was required for this secondary data analysis.\u003c/p\u003e","formattedTitle":"\u003cp\u003eDecoding the multiregional atlas of Parkinson's disease at single-cell resolution\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[{"identity":"18cdf768-be4a-4d4c-a569-f9d258436c71","identifier":"10.13039/501100011011","name":"Junta de Andalucía","awardNumber":"ProyExcel_00978","order_by":0},{"identity":"75f1e59a-1053-4e80-ae97-b81ae56c6712","identifier":"10.13039/501100011033","name":"Agencia Estatal de Investigación","awardNumber":"PID2023-152976NB-I00","order_by":1},{"identity":"de1adefa-aaac-4966-9ce8-60a6db112fe6","identifier":"10.13039/501100011033","name":"Agencia Estatal de Investigación","awardNumber":"RYC2024-049532-I","order_by":2},{"identity":"ebe2b85d-26b1-467d-9b8f-5d26f1527efa","identifier":"10.13039/501100011033","name":"Agencia Estatal de Investigación","awardNumber":"JDC2024-053114-I","order_by":3}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Universitat Politècnica de València","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Parkinson's disease, snRNA-Seq, brain atlas, computational neuroscience","lastPublishedDoi":"10.21203/rs.3.rs-9220144/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9220144/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCharacterizing the multiregional cellular landscape of Parkinson's disease (PD) is essential for understanding its broad impact beyond the midbrain. To advance that goal, we analyzed single-nucleus RNA sequencing data from over 2.2 million nuclei across five brain regions from 93 donors. Compositional analysis identified region-specific alterations, including a reduction in layer 2/3 excitatory neurons in the primary motor cortex and an expansion of specific astrocyte, microglial and oligodendrocyte precursor subtypes in the dorsal motor nucleus of the vagus (DMNX). Differential expression analysis revealed that while most transcriptional changes are cell-type-specific, a core set of markers including BNIP3L, WSB1 and the non-coding RNA LINC00862 are ubiquitously dysregulated across lineages. Furthermore, glial and vascular populations in the DMNX exhibit convergent transcriptional profiles characterized by mitochondrial dysfunction, neuroinflammation and extracellular matrix remodeling. These results provide a high-resolution characterization of the molecular and cellular changes in PD, demonstrating that disease-associated alterations are highly dependent on the intersection of cell identity and anatomical location.\u003c/p\u003e","manuscriptTitle":"Decoding the multiregional atlas of Parkinson's disease at single-cell resolution","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-02 07:32:35","doi":"10.21203/rs.3.rs-9220144/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e218f9f3-d98a-45dd-9662-5fcccc78c83f","owner":[],"postedDate":"April 2nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":65103639,"name":"Computational Neuroscience"}],"tags":[],"updatedAt":"2026-04-02T07:32:35+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-02 07:32:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9220144","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9220144","identity":"rs-9220144","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}