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Using cryo-electron microscopy, we determined the structure of an S320F\n                  <jats:sub>295-330<\/jats:sub>\n                  tau fibril composed of parallel chains stabilized by the\n                  <jats:sup>306<\/jats:sup>\n                  VQIVYK\n                  <jats:sup>311<\/jats:sup>\n                  amyloid motif, with S320F buried in the fibril core and a C322-C322 disulfide linking two protofilaments. Although cysteines are dispensable for fibril formation by isolated peptide fragments in vitro, tau repeat domain constructs containing both C291 and C322 generate more potent seeds in cellular assays. In contrast, the C322S mutation suppresses spontaneous aggregation of S320F tau in cells, and combined C291S and C322S mutations inhibit seeded aggregation in both wild-type and S320F contexts. Systematic alanine mutagenesis coupled with seeding by tauopathy-derived material identifies cysteine residues as critical determinants of tau seeding, comparable in importance to core amyloid motifs. Together, these findings establish cysteines as central chemical regulators of tau aggregation and propagation.\n                <\/jats:p>","DOI":"10.64898\/2026.03.12.711133","type":"posted-content","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T21:50:12Z","timestamp":1773697812000},"source":"Crossref","is-referenced-by-count":3,"title":["Cysteines are critical determinants of spontaneous and seeded tau aggregation in cells"],"prefix":"10.64898","author":[{"given":"Parvathy","family":"Jayan","sequence":"first","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Peter O\u2019Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1839-1663","authenticated-orcid":false,"given":"Simran","family":"Rastogi","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative 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