{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:49:42Z","timestamp":1782280182715,"version":"3.54.5"},"posted":{"date-parts":[[2025,4,3]]},"group-title":"Neuroscience","reference-count":87,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\u03b1-Synuclein (\u03b1Syn) can misfold and aggregate to form fibrillar \u00df-sheet-rich aggregates (\u201cstrains\u201d) that are phosphorylated (p-\u03b1Syn) and deposited into intracellular inclusions in the brain, the pathological hallmark of synucleinopathies including Parkinson\u2019s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Previously, we reported that seed amplification assays such as real-time quaking-induced conversion (RT-QuIC) amplifies and detects \u03b1Syn strains from the patient skin. However, whether skin-derived \u03b1Syn strains induce disease-specific pathological features in a biological system is unknown.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We generated a U251 human glioblastoma cell line expressing fluorescently tagged \u03b1Syn carrying the PD-linked A53T mutation and F\u00f6rster resonance energy transfer (FRET)-based U251 biosensor cells. Using fluorescence microscopy coupled with\n                    <jats:italic>in situ<\/jats:italic>\n                    detergent extraction, FRET-Flow cytometry and high-content confocal imaging, we examined the pathological burden and morphology of p-\u03b1Syn inclusions seeded by RT-QuIC-amplified patient skin and brain \u03b1Syn strains in \u03b1Syn-expressing U251 cells, FRET-based \u03b1Syn biosensor cells and \u03b1Syn biosensor cell-derived neurons.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    U251 cells allow robust and rapid\n                    <jats:italic>in situ<\/jats:italic>\n                    detection of detergent-insoluble intracellular \u03b1Syn inclusions triggered by exogenous \u03b1Syn seeds. In U251 FRET-based biosensor cells, PD skin-amplified strains induce a greater pathological burden and distinct p-\u03b1Syn inclusion morphology from PD brain-amplified and DLB skin-amplified strains. Inclusion morphology of DLB and MSA skin- and brain-amplified strains are comparable. Furthermore, skin-amplified \u03b1Syn strains induce neuronal inclusions and cause degeneration of induced neurons reprogrammed from the U251 biosensor cells. Finally, biosensor cell-propagated PD skin \u03b1Syn strains induce higher seeding activity measured by RT-QuIC than PD brain and DLB skin \u03b1Syn strains, linking intracellular pathological burden to\n                    <jats:italic>in vitro<\/jats:italic>\n                    seeding activity.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>We report the detection of distinct PD strains derived from patient skin and brain tissues that trigger unique pathological phenotypes in U251 \u03b1Syn biosensor cells and cause degeneration of reprogrammed neurons from the same cell lineage. Moreover, DLB and MSA skin \u03b1Syn strains mimic pathological features of their brain \u03b1Syn strains in these biosensor cells. Therefore, the U251 \u03b1Syn biosensor cell model is a robust tool to potentially discriminate PD and DLB synucleinopathies and to study \u03b1Syn tissue- and strain-specific etiology and pathogenesis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"646513v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.04.01.646513","type":"posted-content","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T21:40:11Z","timestamp":1743716411000},"source":"Crossref","is-referenced-by-count":0,"title":["Distinct alpha-synuclein strains derived from Parkinson\u2019s disease patient tissues trigger differential inclusion pathology in a novel biosensor cell model"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9995-9219","authenticated-orcid":false,"given":"Anupam","family":"Raina","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4612-1943","authenticated-orcid":false,"given":"Jose Carlos","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5220-7148","authenticated-orcid":false,"given":"Xiaohui","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7367-5998","authenticated-orcid":false,"given":"Linda","family":"Overstreet-Wadiche","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8180-2061","authenticated-orcid":false,"given":"Jacques I.","family":"Wadiche","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2639-4605","authenticated-orcid":false,"given":"Chun-Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7180-3001","authenticated-orcid":false,"given":"Shu G.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041202040870000_2025.04.01.646513v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/42166"},{"key":"2026041202040870000_2025.04.01.646513v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(97)00336-4"},{"key":"2026041202040870000_2025.04.01.646513v1.3","doi-asserted-by":"crossref","unstructured":"Spillantini MG , Spillantini MG , Crowther RA , Crowther RA , Crowther RA , Jakes R , et al. 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