{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T05:33:25Z","timestamp":1793165605911,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,14]]},"group-title":"Molecular Biology","reference-count":87,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Institutes of Health"},{"name":"U.S. National Science Foundation","award":["NSF\/DMR-2128556"],"award-info":[{"award-number":["NSF\/DMR-2128556"]}],"id":[{"id":"https:\/\/ror.org\/021nxhr62","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The frequent coexistence of \u03b1-synuclein (\u03b1-syn) and amyloid-\u03b2 (A\u03b2) aggregates in neurodegenerative diseases suggests that heterotypic interactions between these amyloidogenic proteins may influence disease progression, yet their molecular consequences remain poorly understood. Here, we investigated how distinct aggregation states of A\u03b242, monomers and preformed fibrils (PFFs), modulate \u03b1-syn fibril formation, structure, and downstream neuronal pathology. Thioflavin T kinetics showed that A\u03b242 monomers delayed \u03b1-syn fibril formation, whereas A\u03b242 PFFs exhibited a trend toward accelerated aggregation, indicating aggregation state-dependent effects on \u03b1-syn aggregation. Negative-stain TEM, proteinase K digestion, and solid-state NMR spectroscopy further demonstrated that both A\u03b242 monomers and PFFs altered \u03b1-syn fibril structure, generating distinct fibril conformations depending on the A\u03b242 concentration and aggregation state. To determine whether these conformational differences influence pathological activity, \u03b1-syn PFF variants generated in the presence of different concentrations of A\u03b242 monomers or PFFs were applied to dopaminergic neuronal cells. \u03b1-Syn fibrils formed in the presence of A\u03b242 PFFs showed greater capacity to induce intraneuronal \u03b1-syn aggregation than \u03b1-syn PFFs, whereas fibrils formed in the presence of A\u03b242 monomers exhibited similar or reduced intraneuronal aggregation-inducing capacity relative to \u03b1-syn PFFs. Together, our findings demonstrate that heterotypic interactions with A\u03b242 reshape \u03b1-syn aggregation pathways and fibril conformations, generating structurally distinct \u03b1-syn fibril populations that vary in their ability to trigger intraneuronal aggregation. These results provide a molecular framework for understanding how cross-talk between amyloidogenic proteins may contribute to structural and pathological heterogeneity in mixed neurodegenerative diseases.<\/jats:p>","DOI":"10.64898\/2026.09.09.750398","type":"posted-content","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:35:12Z","timestamp":1789392912000},"source":"Crossref","is-referenced-by-count":0,"title":["A\u03b242-Driven \u03b1-synuclein Fibril Polymorphism and Distinct Intracellular Aggregation"],"prefix":"10.64898","author":[{"given":"Purnopama","family":"Saha","sequence":"first","affiliation":[{"name":"Department of Electrical and Computer Engineering, Binghamton University, Binghamton, NY 13902, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teshani","family":"Liyanaarachchige","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Drexel University, Philadelphia, PA 19104, United 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