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While this process has been extensively studied in vivo and in vitro, non-physiological reaction conditions of fibril formation in vitro have precluded the identification and mechanistic analysis of cellular proteins, which may alter PrP self-assembly and prion replication. Here, we have developed a fibril formation assay for recombinant murine and human PrP (23-231) under near-native conditions (NAA) to study the effect of cellular proteins, which may be risk factors or potential therapeutic targets in prion disease. Genetic screening suggests that variants that increase syntaxin-6 expression in the brain (gene: STX6) are risk factors for sporadic Creutzfeldt\u2013Jakob disease. Analysis of the protein in NAA revealed, counterintuitively, that syntaxin-6 is a potent inhibitor of PrP fibril formation. It significantly delayed the lag phase of fibril formation at highly sub-stoichiometric molar ratios. However, when assessing toxicity of different aggregation time points to primary neurons, syntaxin-6 prolonged the presence of neurotoxic PrP species. Electron microscopy and super-resolution fluorescence microscopy revealed that, instead of highly ordered fibrils, in the presence of syntaxin-6 PrP formed less-ordered aggregates containing syntaxin-6. These data strongly suggest that the protein can directly alter the initial phase of PrP self-assembly and, uniquely, can act as an \u2018anti-chaperone\u2019, which promotes toxic aggregation intermediates by inhibiting fibril formation.\n                  <\/jats:p>","DOI":"10.7554\/elife.83320","type":"journal-article","created":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T06:15:46Z","timestamp":1723011346000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.83320","source":"Crossref","is-referenced-by-count":6,"title":["Syntaxin-6 delays prion protein fibril formation and prolongs the presence of toxic aggregation intermediates"],"prefix":"10.7554","volume":"13","author":[{"given":"Daljit","family":"Sangar","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043j90n04","id-type":"ROR","asserted-by":"publisher"}],"name":"MRC Prion Unit at UCL, Institute of Prion Diseases","place":["London, United 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