{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:51:39Z","timestamp":1791276699376,"version":"4.1.0"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":278,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurobiol"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    \u03b1-Synuclein (\u03b1Syn) aggregation is a defining pathological feature of synucleinopathies, including Parkinson\u2019s disease, dementia with Lewy bodies, and multiple system atrophy (MSA). However, existing in vitro methods to monitor \u03b1Syn aggregation often rely on endpoint assays that cannot distinguish monomeric from oligomeric species or capture early aggregation dynamics. Here, we implement an \u03b1Syn bimolecular fluorescence complementation (\u03b1Syn-BiFC) strategy in a stable human glial-derived cell system optimized for real-time, high-content analysis of early \u03b1Syn self-association events and their modulation. In this strategy, \u03b1Syn is fused to complementary fragments of the Venus fluorescent protein, enabling real-time visualization of \u03b1Syn-\u03b1Syn interactions during oligomer formation. Using U373 human astrocytoma cells, a scalable glial-derived cell line previously used in studies of MSA, we established both transient and stable \u03b1Syn-BiFC expression systems. We demonstrate that reconstituted Venus fluorescence correlates with pSer129 \u03b1Syn immunostaining, supporting the association of the BiFC signal with pathology-related \u03b1Syn assemblies. The model responded robustly to multiple stressors known to promote \u03b1Syn aggregation, including proteostasis disruption (leupeptin, MG132), ER stress (tunicamycin), and environmental toxins (rotenone), while iron, particularly Fe\n                    <jats:sup>3<\/jats:sup>\n                    \u207a, also enhanced \u03b1Syn self-association. Furthermore, testing two small molecules previously shown to attenuate \u03b1Syn aggregation and pathology in vivo revealed a reduction in Venus fluorescence, consistent with reduced \u03b1Syn self-association and supporting the platform\u2019s utility for drug discovery screens. By providing a dynamic, sensitive, and physiologically relevant readout of early \u03b1Syn assemblies, the \u03b1Syn-BiFC model overcomes limitations of conventional assays and offers a scalable framework for mechanistic studies, compound screening, and integration into more disease-relevant neuronal and aging-enhanced models for future synucleinopathies research.\n                  <\/jats:p>","DOI":"10.1007\/s12035-026-06248-2","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:37:34Z","timestamp":1791268654000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Live-Cell Imaging System for the Identification of Pro- and Anti-Aggregatory \u03b1-Synuclein Modulators"],"prefix":"10.1007","volume":"63","author":[{"given":"Tzukit","family":"Tal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Almog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ortal Iancu","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihi","family":"Radomir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Bar-On","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ianai","family":"Fishbein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4777-986X","authenticated-orcid":false,"given":"Eran","family":"Meshorer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"6248_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26115405","volume":"26","author":"O Arias-Carri\u00f3n","year":"2025","unstructured":"Arias-Carri\u00f3n O, Guerra-Crespo M, Padilla-God\u00ednez FJ, Soto-Rojas LO, Manjarrez E (2025) \u03b1-Synuclein pathology in synucleinopathies: mechanisms, biomarkers, and therapeutic challenges. 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