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PrP<jats:sup>Sc<\/jats:sup> assemblies encode distinct biochemical and biological properties. They harbor a specific profile of PrP<jats:sup>Sc<\/jats:sup> species, from small oligomers to fibrils in different ratios, where the highest infectivity aligns with oligomeric particles. To investigate the impact of PrP<jats:sup>Sc<\/jats:sup> aggregate complexity on prion propagation, biochemical properties, and disease pathogenesis, we fractionated elk prions by sedimentation velocity centrifugation, followed by sub-passages of individual fractions in cervidized mice. Upon first passage, different fractions generated PrP<jats:sup>Sc<\/jats:sup> with distinct biochemical, biophysical, and neuropathological profiles. Notably, low or high molecular weight PrP<jats:sup>Sc<\/jats:sup> aggregates caused different clinical signs of hyperexcitability or lethargy, respectively, which were retained over passage, whereas other properties converged. Our findings suggest that PrP<jats:sup>Sc<\/jats:sup> quaternary structure determines an initial selection of a specific replication environment, resulting in transmissible features that are independent of PrP<jats:sup>Sc<\/jats:sup> biochemical and biophysical properties.<\/jats:p>","DOI":"10.1038\/s42003-023-05541-3","type":"journal-article","created":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T07:02:09Z","timestamp":1699945329000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Propagation of PrPSc in mice reveals impact of aggregate composition on prion disease pathogenesis"],"prefix":"10.1038","volume":"6","author":[{"given":"Sheng Chun","family":"Chang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samia","family":"Hannaoui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Immaculata","family":"Arifin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan-Hung","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinli","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5102-8706","authenticated-orcid":false,"given":"Holger","family":"Wille","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5923-3464","authenticated-orcid":false,"given":"Sabine","family":"Gilch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,11,14]]},"reference":[{"key":"5541_CR1","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1146\/annurev.neuro.24.1.519","volume":"24","author":"J Collinge","year":"2001","unstructured":"Collinge, J. 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