{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:11:06Z","timestamp":1790878266128,"version":"4.1.0"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"5","license":[{"start":{"date-parts":[[2022,7,26]],"date-time":"2022-07-26T00:00:00Z","timestamp":1658793600000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["5R21NS109871-02"],"award-info":[{"award-number":["5R21NS109871-02"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:p>The intracellular misfolding and accumulation of alpha-synuclein into structures collectively called Lewy pathology (LP) is a central phenomenon for the pathogenesis of synucleinopathies, including Parkinson\u2019s disease (PD) and dementia with Lewy bodies (DLB). Understanding the molecular architecture of LP is crucial for understanding synucleinopathy disease origins and progression. Here we used a technique called biotinylation by antibody recognition (BAR) to label total (BAR-SYN1) and pathological alpha-synuclein (BAR-PSER129) in situ for subsequent mass spectrometry analysis. Results showed superior immunohistochemical detection of LP following the BAR-PSER129 protocol, particularly for fibers and punctate pathology within the striatum and cortex. Mass spectrometry analysis of BAR-PSER129\u2013labeled LP identified 261 significantly enriched proteins in the synucleinopathy brain when compared to nonsynucleinopathy brains. In contrast, BAR-SYN1 did not differentiate between disease and nonsynucleinopathy brains. Pathway analysis of BAR-PSER129\u2013enriched proteins revealed enrichment for 718 pathways; notably, the most significant KEGG pathway was PD, and Gene Ontology (GO) cellular compartments were the vesicle, extracellular vesicle, extracellular exosome, and extracellular organelle. Pathway clustering revealed several superpathways, including metabolism, mitochondria, lysosome, and intracellular vesicle transport. Validation of the BAR-PSER129\u2013identified protein hemoglobin beta (HBB) by immunohistochemistry confirmed the interaction of HBB with PSER129 Lewy neurites and Lewy bodies. In summary, BAR can be used to enrich for LP from formalin-fixed human primary tissues, which allowed the determination of molecular signatures of LP. This technique has broad potential to help understand the phenomenon of LP in primary human tissue and animal models.<\/jats:p>","DOI":"10.1073\/pnas.2114405119","type":"journal-article","created":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T16:20:11Z","timestamp":1643214011000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":59,"title":["In situ proximity labeling identifies Lewy pathology molecular interactions in the human brain"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8043-8517","authenticated-orcid":false,"given":"Bryan A.","family":"Killinger","sequence":"first","affiliation":[{"name":"Graduate College, Rush University Medical Center, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee L.","family":"Marshall","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diptaman","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Chu","sequence":"additional","affiliation":[{"name":"ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ 85287"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Bras","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Guerreiro","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey H.","family":"Kordower","sequence":"additional","affiliation":[{"name":"ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ 85287"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,1,26]]},"reference":[{"key":"e_1_3_5_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-013-8489-4"},{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep05797"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.141952"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2012.11.020"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2012.00585.x"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1913904117"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.24468"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.2741\/2973"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2007.00048.x"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4533"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0710346105"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201200279"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.529578"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1827.1999.00875.x"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1177\/40.10.1527370"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.24195"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0423-2"},{"key":"e_1_3_5_18_2","first-page":"879","article-title":"Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson\u2019s disease and dementia with Lewy bodies","volume":"152","author":"Baba M.","year":"1998","unstructured":"M. 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