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Historically, aggregation of a single protein was observed to be correlated with these different pathologies: tau in AD and \u03b1-synuclein (\u03b1S) in PD. However, there is increasing evidence that the pathologies of these two diseases overlap, and the individual proteins may even promote each other\u2019s aggregation. Both tau and \u03b1S are intrinsically disordered proteins (IDPs), lacking stable secondary and tertiary structure under physiological conditions. In this study we used a combination of biochemical and biophysical techniques to interrogate the interaction of tau with both soluble and fibrillar \u03b1S. Fluorescence correlation spectroscopy (FCS) was used to assess the interactions of specific domains of fluorescently labeled tau with full length and C-terminally truncated \u03b1S in both monomer and fibrillar forms. We found that full-length tau as well as individual tau domains interact with monomer \u03b1S weakly, but this interaction is much more pronounced with \u03b1S aggregates. \u03b1S aggregates also mildly slow the rate of tau aggregation, although not the final degree of aggregation. Our findings suggest that co-occurrence of tau and \u03b1S in disease are more likely to occur through monomer-fiber binding interactions, rather than monomer-monomer or co-aggregation.<\/jats:p>","DOI":"10.1371\/journal.pone.0309416","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T17:29:56Z","timestamp":1725989396000},"page":"e0309416","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Multivalency drives interactions of alpha-synuclein fibrils with tau"],"prefix":"10.1371","volume":"19","author":[{"given":"Jennifer","family":"Ramirez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3263-7671","authenticated-orcid":true,"given":"Ibrahim G.","family":"Saleh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan S. 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