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To identify and characterize selectively vulnerable brain cell populations in PD, we performed single-nucleus transcriptomics and unbiased proteomics to profile the prefrontal cortex from postmortem human brains of six individuals with late-stage PD and six age-matched controls. Analysis of nearly 80,000 nuclei led to the identification of eight major brain cell types, including elevated brain-resident T cells in PD, each with distinct transcriptional changes in agreement with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem brain tissues, we found that \u03b1-synuclein pathology was inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in the prefrontal cortex that were preferentially down-regulated in PD. By comparing this single-cell PD dataset with a published analysis of similar brain regions in Alzheimer\u2019s disease (AD), we found no common differentially expressed genes in neurons but identified many shared differentially expressed genes in glial cells, suggesting that the disease etiologies, especially in the context of neuronal vulnerability, in PD and AD are likely distinct.<\/jats:p>","DOI":"10.1126\/scitranslmed.abo1997","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T13:59:03Z","timestamp":1730296743000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":84,"title":["Single-cell transcriptomic and proteomic analysis of Parkinson\u2019s disease brains"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7428-6297","authenticated-orcid":true,"given":"Biqing","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA."},{"name":"Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9770-7197","authenticated-orcid":true,"given":"Jae-Min","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA."},{"name":"Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3631-2228","authenticated-orcid":true,"given":"Sarah R.","family":"Coffey","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA."},{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0623-6618","authenticated-orcid":true,"given":"Anthony","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4089-6601","authenticated-orcid":true,"given":"I-Uen","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA."},{"name":"Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2627-4897","authenticated-orcid":true,"given":"Jiawei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA."},{"name":"Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8704-1512","authenticated-orcid":true,"given":"Chang","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA."},{"name":"Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, GA 30322, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA."},{"name":"Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA."},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4850-3462","authenticated-orcid":true,"given":"TuKiet T.","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry and Keck MS &amp; Proteomics Resource, Yale University, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4708-8479","authenticated-orcid":true,"given":"Pallavi P.","family":"Gopal","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1797-4288","authenticated-orcid":true,"given":"Stephen D.","family":"Ginsberg","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA."},{"name":"Departments of Psychiatry, Neuroscience &amp; Physiology, and NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1195-9607","authenticated-orcid":true,"given":"Hongyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4664-535X","authenticated-orcid":true,"given":"David A.","family":"Hafler","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA."},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA."},{"name":"Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9035-1733","authenticated-orcid":true,"given":"Sreeganga S.","family":"Chandra","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA."},{"name":"Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA."},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4860-831X","authenticated-orcid":true,"given":"Le","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA."},{"name":"Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA."},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.13"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10561-008-9067-2"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2019.07.004"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"e_1_3_2_6_2","first-page":"368","article-title":"Single-cell RNA sequencing in Parkinson\u2019s disease","volume":"9","author":"Ma S.-X.","year":"2021","unstructured":"S.-X. 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