{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:18:23Z","timestamp":1785424703199,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,7]]},"group-title":"Neuroscience","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01NS114409"],"award-info":[{"award-number":["R01NS114409"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U24AG079685"],"award-info":[{"award-number":["U24AG079685"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/03arq3225","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Synucleinopathies, including Parkinson\u2019s disease, are neurodegenerative diseases characterized by intracellular inclusions containing the amyloidogenic protein alpha-synuclein. While classically considered to be brain disorders, increasing evidence suggests involvement of the gut, with alpha-synuclein aggregates potentially propagating to the brain via the vagus nerve. Evidence also suggests that the vermiform appendix is particularly susceptible to alpha-synuclein aggregation, and appendectomy impacts the onset of Parkinson\u2019s disease. However, the mechanisms underlying the aggregation of alpha-synuclein in the vermiform appendix remains poorly understood. To explore this, we assessed aggregation properties in postmortem appendix tissues from healthy controls and synucleinopathy patients using the alpha-synuclein seed amplification assay (alpha-synuclein-SAA) and performed total RNA sequencing alongside differential bisulfite-hybridization-based DNA methylation analysis in the same tissues to investigate the molecular underpinnings. Moreover, we determined alpha-synuclein cleavage patterns by cataloging soluble alpha-synuclein proteoforms from postmortem substantia nigra and post-surgical appendix tissues using top-down mass spectrometry (TD-MS). Alpha-synuclein-SAA was positive in appendix samples for 68.75% of synucleinopathy patients and 6.6% of controls. Genomic profiling revealed dysregulated expression of genes linked to protein folding\/degradation, immune\/inflammatory responses, and ciliary dynamics in synucleinopathy appendix tissues. TD-MS identified 65 distinct alpha-synuclein proteoforms in the substantia nigra and appendix, with 9 unique to the appendix. Further,\n                  <jats:italic>in silico<\/jats:italic>\n                  modeling revealed higher aggregation propensity of alpha-synuclein proteoforms in the appendix versus substantia nigra. Together, our findings suggest that a tissue environment of alpha-synuclein dysproteostasis in the appendix has the potential to contribute to the development of synucleinopathies.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>Appendixes from synucleinopathy patients show altered gene expression, unique \u03b1-syn proteoforms, and higher aggregation propensity than substantia nigra.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.07.680938","type":"posted-content","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T05:06:09Z","timestamp":1759899969000},"source":"Crossref","is-referenced-by-count":0,"title":["Aggregation-prone alpha-synuclein proteoforms and dysregulated molecular signatures in the vermiform appendix of synucleinopathy patients"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2172-4895","authenticated-orcid":false,"given":"Ehraz","family":"Anis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9595-9609","authenticated-orcid":false,"given":"Saima","family":"Zameer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Wierenga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peipei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacek W.","family":"Sikora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3190-6721","authenticated-orcid":false,"given":"Juozas","family":"Gordevicius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan","family":"Schilthuis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard D.","family":"LeDuc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5524-2044","authenticated-orcid":false,"given":"Jeffery H.","family":"Kordower","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Pinho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Pritzkow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Soto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2924-5186","authenticated-orcid":false,"given":"Patrik","family":"Brundin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8327-6242","authenticated-orcid":false,"given":"Lena","family":"Brundin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8043-8517","authenticated-orcid":false,"given":"BA","family":"Killinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025101009551056000_2025.10.07.680938v1.1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110551200"},{"key":"2025101009551056000_2025.10.07.680938v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-019-02057-1"},{"key":"2025101009551056000_2025.10.07.680938v1.3","doi-asserted-by":"crossref","first-page":"666585","DOI":"10.3389\/fchem.2021.666585","article-title":"\u03b1-Synuclein: An All-Inclusive Trip Around its Structure, Influencing Factors and Applied Techniques","volume":"9","year":"2021","journal-title":"Front Chem"},{"key":"2025101009551056000_2025.10.07.680938v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(02)00065-9"},{"key":"2025101009551056000_2025.10.07.680938v1.5","doi-asserted-by":"crossref","unstructured":"H. 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