{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:27:19Z","timestamp":1787164039071,"version":"build-2736575974"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Increased expression of syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed genetic risk mechanism for sporadic prion disease and progressive supranuclear palsy, as well as being implicated in Alzheimer\u2019s disease. However, no study has validated its functional role in prion disease, its mechanism of action nor explored the disease stage at which it is acting. Here, we show that syntaxin-6 knockdown in cellular models increases cell-associated infectivity, whilst overexpression produces the opposite effect. This observation is broadly consistent across multiple cell types and prion strains. Furthermore, syntaxin-6 knockdown leads to an accumulation of perinuclear disease-related PrP, consistent with a trafficking mechanism, and alters the morphology of disease-related PrP. We demonstrate that syntaxin-6 knockdown reduces the secretion of prions from infected cells, which provides a mechanism for the prion-related cellular phenotypes observed. Complementary in vivo studies showed that syntaxin-6 influences early stages of prion disease in experimental mice, increasing transmission risk after inoculation with low prion doses. Conversely, syntaxin-6 does not affect prion propagation kinetics or toxicity during established disease. Taken together, our studies firmly establish syntaxin-6 as a modifier of prion pathogenesis with a role in prion trafficking and export. Our findings further suggest that syntaxin-6 modifies the risk of the establishment of disease in line with its genetic association in humans. Thus, this work provides important insights into the role of a pleiotropic prion\/prion-like modifier, grounded in human genetics evidence, which may have wider relevance to other neurodegenerative diseases.<\/jats:p>","DOI":"10.1007\/s00401-025-02946-8","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T04:52:31Z","timestamp":1762231951000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Intracellular trafficking SNARE protein, syntaxin-6, modifies prion cellular phenotypes and risk of disease development in vivo"],"prefix":"10.1007","volume":"150","author":[{"given":"Elizabeth","family":"Hill","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitali M.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan M.","family":"Ribes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Linehan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuquan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Jakubcova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyma","family":"Hamdan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Tomlinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Ercolani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parvin","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Thirlway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Argentina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline T.","family":"Marinho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Kaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Fitzhugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham S.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Brandner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter-Christian","family":"Kl\u00f6hn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Collinge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Cunningham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Mead","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"2946_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21207763","author":"RN Alves","year":"2020","unstructured":"Alves RN, Iglesia RP, Prado MB, Melo Escobar MI, Boccacino JM, Fernandes CFL et al (2020) A new take on prion protein dynamics in cellular trafficking. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms21207763","journal-title":"Int J Mol Sci"},{"key":"2946_CR2","doi-asserted-by":"publisher","first-page":"214","DOI":"10.2307\/2347041","volume":"26","author":"J Baptista","year":"1977","unstructured":"Baptista J, Pike MC (1977) Algorithm AS 115: exact two-sided confidence limits for the odds ratio in a 2 \u00d7 2 table. J Roy Stat Soc: Ser C (Appl Stat) 26:214\u2013220. https:\/\/doi.org\/10.2307\/2347041","journal-title":"J Roy Stat Soc: Ser C (Appl Stat)"},{"key":"2946_CR3","doi-asserted-by":"publisher","first-page":"23815","DOI":"10.1073\/pnas.2007406117","volume":"117","author":"I Benilova","year":"2020","unstructured":"Benilova I, Reilly M, Terry C, Wenborn A, Schmidt C, Marinho AT et al (2020) Highly infectious prions are not directly neurotoxic. Proc Natl Acad Sci 117:23815. https:\/\/doi.org\/10.1073\/pnas.2007406117","journal-title":"Proc Natl Acad Sci"},{"key":"2946_CR4","doi-asserted-by":"publisher","unstructured":"Bhamra S, Arora P, Manka SW, Schmidt C, Brown C, Rayner MLD, Kl\u00f6hn P-C, Clarke AR, Collinge J, Jat PS (2022) Prion propagation is dependent on key amino acids in Charge cluster 2 within the prion protein. bioRxiv. https:\/\/doi.org\/10.1101\/2022.08.08.503133","DOI":"10.1101\/2022.08.08.503133"},{"key":"2946_CR5","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1091\/mbc.8.7.1261","volume":"8","author":"JB Bock","year":"1997","unstructured":"Bock JB, Klumperman J, Davanger S, Scheller RH (1997) Syntaxin 6 functions in trans-Golgi network vesicle trafficking. Mol Biol Cell 8:1261\u20131271. https:\/\/doi.org\/10.1091\/mbc.8.7.1261","journal-title":"Mol Biol Cell"},{"key":"2946_CR6","doi-asserted-by":"publisher","first-page":"17961","DOI":"10.1074\/jbc.271.30.17961","volume":"271","author":"JB Bock","year":"1996","unstructured":"Bock JB, Lin RC, Scheller RH (1996) A new syntaxin family member implicated in targeting of intracellular transport vesicles. J Biol Chem 271:17961\u201317965. https:\/\/doi.org\/10.1074\/jbc.271.30.17961","journal-title":"J Biol Chem"},{"key":"2946_CR7","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1038\/s41593-022-01128-z","volume":"25","author":"J Bryois","year":"2022","unstructured":"Bryois J, Calini D, Macnair W, Foo L, Urich E, Ortmann W et al (2022) Cell-type-specific cis-eQTLs in eight human brain cell types identify novel risk genes for psychiatric and neurological disorders. Nat Neurosci 25:1104\u20131112. https:\/\/doi.org\/10.1038\/s41593-022-01128-z","journal-title":"Nat Neurosci"},{"key":"2946_CR8","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1016\/s0140-6736(61)92008-6","volume":"1","author":"RL Chandler","year":"1961","unstructured":"Chandler RL (1961) Encephalopathy in mice produced by inoculation with scrapie brain material. Lancet 1:1378\u20131379. https:\/\/doi.org\/10.1016\/s0140-6736(61)92008-6","journal-title":"Lancet"},{"key":"2946_CR9","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-018-0270-8","author":"JA Chen","year":"2018","unstructured":"Chen JA, Chen Z, Won H, Huang AY, Lowe JK, Wojta K et al (2018) Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases. Mol Neurodegen. https:\/\/doi.org\/10.1186\/s13024-018-0270-8","journal-title":"Mol Neurodegen"},{"key":"2946_CR10","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1002\/mds.27702","volume":"34","author":"Z Chen","year":"2019","unstructured":"Chen Z, Chen JA, Shatunov A, Jones AR, Kravitz SN, Huang AY et al (2019) Genome-wide survey of copy number variants finds MAPT duplications in progressive supranuclear palsy. Mov Disord Off J Mov Disord Soc 34:1049\u20131059. https:\/\/doi.org\/10.1002\/mds.27702","journal-title":"Mov Disord Off J Mov Disord Soc"},{"key":"2946_CR11","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21197016","author":"P Cherry","year":"2020","unstructured":"Cherry P, Gilch S (2020) The role of vesicle trafficking defects in the pathogenesis of prion and prion-like disorders. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms21197016","journal-title":"Int J Mol Sci"},{"key":"2946_CR12","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/nature20415","volume":"539","author":"J Collinge","year":"2016","unstructured":"Collinge J (2016) Mammalian prions and their wider relevance in neurodegenerative diseases. Nature 539:217\u2013226. https:\/\/doi.org\/10.1038\/nature20415","journal-title":"Nature"},{"key":"2946_CR13","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1126\/science.1138718","volume":"318","author":"J Collinge","year":"2007","unstructured":"Collinge J, Clarke AR (2007) A general model of prion strains and their pathogenicity. Science (New York, NY) 318:930\u2013936. https:\/\/doi.org\/10.1126\/science.1138718","journal-title":"Science (New York, NY)"},{"key":"2946_CR14","doi-asserted-by":"publisher","first-page":"9295","DOI":"10.1073\/pnas.151242598","volume":"98","author":"M Enari","year":"2001","unstructured":"Enari M, Flechsig E, Weissmann C (2001) Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody. Proc Natl Acad Sci 98:9295\u20139299. https:\/\/doi.org\/10.1073\/pnas.151242598","journal-title":"Proc Natl Acad Sci"},{"key":"2946_CR15","doi-asserted-by":"publisher","first-page":"7880","DOI":"10.1038\/s41467-024-52025-x","volume":"15","author":"K Farrell","year":"2024","unstructured":"Farrell K, Humphrey J, Chang T, Zhao Y, Leung YY, Kuksa PP et al (2024) Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes. Nat Commun 15:7880. https:\/\/doi.org\/10.1038\/s41467-024-52025-x","journal-title":"Nat Commun"},{"key":"2946_CR16","doi-asserted-by":"publisher","first-page":"1514.e1511","DOI":"10.1016\/j.neurobiolaging.2014.01.010","volume":"35","author":"R Ferrari","year":"2014","unstructured":"Ferrari R, Ryten M, Simone R, Trabzuni D, Nicolaou N, Hondhamuni G et al (2014) Assessment of common variability and expression quantitative trait loci for genome-wide associations for progressive supranuclear palsy. Neurobiol Aging 35:1514.e1511-1514.e1511. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2014.01.010","journal-title":"Neurobiol Aging"},{"key":"2946_CR17","doi-asserted-by":"publisher","first-page":"9683","DOI":"10.1073\/pnas.0308413101","volume":"101","author":"B Fevrier","year":"2004","unstructured":"Fevrier B, Vilette D, Archer F, Loew D, Faigle W, Vidal M et al (2004) Cells release prions in association with exosomes. Proc Natl Acad Sci 101:9683\u20139688. https:\/\/doi.org\/10.1073\/pnas.0308413101","journal-title":"Proc Natl Acad Sci"},{"key":"2946_CR18","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1016\/j.neuron.2018.08.010","volume":"99","author":"FF Heisler","year":"2018","unstructured":"Heisler FF, Pechmann Y, Wieser I, Altmeppen HC, Veenendaal L, Muhia M et al (2018) Muskelin coordinates PrP(C) lysosome versus exosome targeting and impacts prion disease progression. Neuron 99:1155-1169.e1159. https:\/\/doi.org\/10.1016\/j.neuron.2018.08.010","journal-title":"Neuron"},{"key":"2946_CR19","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1038\/ng.859","volume":"43","author":"GU H\u00f6glinger","year":"2011","unstructured":"H\u00f6glinger GU, Melhem NM, Dickson DW, Sleiman PMA, Wang L-S, Klei L et al (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699\u2013705. https:\/\/doi.org\/10.1038\/ng.859","journal-title":"Nat Genet"},{"key":"2946_CR20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0304528","volume":"19","author":"H Hummerich","year":"2024","unstructured":"Hummerich H, Speedy H, Campbell T, Darwent L, Hill E, Collins S et al (2024) Genome wide association study of clinical duration and age at onset of sporadic CJD. PLoS ONE 19:e0304528. https:\/\/doi.org\/10.1371\/journal.pone.0304528","journal-title":"PLoS ONE"},{"key":"2946_CR21","doi-asserted-by":"publisher","unstructured":"Ito SI, Tanaka Y (2024) Evaluation of LC3-II Release via extracellular vesicles in relation to the accumulation of intracellular LC3-positive Vesicles. J Vis Exp. https:\/\/doi.org\/10.3791\/67385","DOI":"10.3791\/67385"},{"key":"2946_CR22","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2024.106599","author":"D Jiang","year":"2024","unstructured":"Jiang D, Nan H, Chen Z, Zou W-Q, Wu L (2024) Genetic insights into drug targets for sporadic Creutzfeldt\u2013Jakob disease: integrative multi-omics analysis. Neurobiol Dis. https:\/\/doi.org\/10.1016\/j.nbd.2024.106599","journal-title":"Neurobiol Dis"},{"key":"2946_CR23","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106363","volume":"190","author":"E Jones","year":"2024","unstructured":"Jones E, Hill E, Linehan J, Nazari T, Caulder A, Codner GF et al (2024) Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt\u2013Jakob disease risk gene Stx6. Neurobiol Dis 190:106363. https:\/\/doi.org\/10.1016\/j.nbd.2023.106363","journal-title":"Neurobiol Dis"},{"key":"2946_CR24","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1016\/s1474-4422(20)30273-8","volume":"19","author":"E Jones","year":"2020","unstructured":"Jones E, Hummerich H, Vir\u00e9 E, Uphill J, Dimitriadis A, Speedy H et al (2020) Identification of novel risk loci and causal insights for sporadic Creutzfeldt\u2013Jakob disease: a genome-wide association study. Lancet Neurol 19:840\u2013848. https:\/\/doi.org\/10.1016\/s1474-4422(20)30273-8","journal-title":"Lancet Neurol"},{"key":"2946_CR25","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1038\/s41593-018-0238-6","volume":"21","author":"M Jucker","year":"2018","unstructured":"Jucker M, Walker LC (2018) Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. Nat Neurosci 21:1341\u20131349. https:\/\/doi.org\/10.1038\/s41593-018-0238-6","journal-title":"Nat Neurosci"},{"key":"2946_CR26","doi-asserted-by":"publisher","first-page":"11666","DOI":"10.1073\/pnas.1834432100","volume":"100","author":"PC Kl\u00f6hn","year":"2003","unstructured":"Kl\u00f6hn PC, Stoltze L, Flechsig E, Enari M, Weissmann C (2003) A quantitative, highly sensitive cell-based infectivity assay for mouse scrapie prions. Proc Natl Acad Sci USA 100:11666\u201311671. https:\/\/doi.org\/10.1073\/pnas.1834432100","journal-title":"Proc Natl Acad Sci USA"},{"key":"2946_CR27","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaf032","author":"F K\u00fc\u00e7\u00fckali","year":"2025","unstructured":"K\u00fc\u00e7\u00fckali F, Hill E, Watzeels T, Hummerich H, Campbell T, Darwent L et al (2025) Multiomic analyses direct hypotheses for Creutzfeldt\u2013Jakob disease risk genes. Brain. https:\/\/doi.org\/10.1093\/brain\/awaf032","journal-title":"Brain"},{"key":"2946_CR28","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1002\/ana.25530","volume":"86","author":"G Leonenko","year":"2019","unstructured":"Leonenko G, Shoai M, Bellou E, Sims R, Williams J, Hardy J et al (2019) Genetic risk for alzheimer disease is distinct from genetic risk for amyloid deposition. Ann Neurol 86:427\u2013435. https:\/\/doi.org\/10.1002\/ana.25530","journal-title":"Ann Neurol"},{"key":"2946_CR29","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1038\/s41588-021-00847-6","volume":"53","author":"G Liu","year":"2021","unstructured":"Liu G, Peng J, Liao Z, Locascio JJ, Corvol JC, Zhu F et al (2021) Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson\u2019s disease. Nat Genet 53:787\u2013793. https:\/\/doi.org\/10.1038\/s41588-021-00847-6","journal-title":"Nat Genet"},{"key":"2946_CR30","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.15252\/embj.201387150","volume":"33","author":"MM Marbiah","year":"2014","unstructured":"Marbiah MM, Harvey A, West BT, Louzolo A, Banerjee P, Alden J et al (2014) Identification of a gene regulatory network associated with prion replication. EMBO J 33:1527\u20131547. https:\/\/doi.org\/10.15252\/embj.201387150","journal-title":"EMBO J"},{"key":"2946_CR31","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/s1474-4422(22)00082-5","volume":"21","author":"S Mead","year":"2022","unstructured":"Mead S, Khalili-Shirazi A, Potter C, Mok T, Nihat A, Hyare H et al (2022) Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt\u2013Jakob disease: evaluation of a first-in-human treatment programme. Lancet Neurol 21:342\u2013354. https:\/\/doi.org\/10.1016\/s1474-4422(22)00082-5","journal-title":"Lancet Neurol"},{"key":"2946_CR32","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1038\/s41586-024-07316-0","volume":"629","author":"EV Minikel","year":"2024","unstructured":"Minikel EV, Painter JL, Dong CC, Nelson MR (2024) Refining the impact of genetic evidence on clinical success. Nature 629:624\u2013629. https:\/\/doi.org\/10.1038\/s41586-024-07316-0","journal-title":"Nature"},{"key":"2946_CR33","doi-asserted-by":"publisher","first-page":"10615","DOI":"10.1093\/nar\/gkaa616","volume":"48","author":"EV Minikel","year":"2020","unstructured":"Minikel EV, Zhao HT, Le J, O\u2019Moore J, Pitstick R, Graffam S et al (2020) Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints. Nucleic Acids Res 48:10615\u201310631. https:\/\/doi.org\/10.1093\/nar\/gkaa616","journal-title":"Nucleic Acids Res"},{"key":"2946_CR34","doi-asserted-by":"publisher","first-page":"17708","DOI":"10.1038\/s41598-022-21820-1","volume":"12","author":"MA Mortberg","year":"2022","unstructured":"Mortberg MA, Vallabh SM, Minikel EV (2022) Disease stages and therapeutic hypotheses in two decades of neurodegenerative disease clinical trials. Sci Rep 12:17708. https:\/\/doi.org\/10.1038\/s41598-022-21820-1","journal-title":"Sci Rep"},{"key":"2946_CR35","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1038\/ng.3314","volume":"47","author":"MR Nelson","year":"2015","unstructured":"Nelson MR, Tipney H, Painter JL, Shen J, Nicoletti P, Shen Y et al (2015) The support of human genetic evidence for approved drug indications. Nat Genet 47:856\u2013860. https:\/\/doi.org\/10.1038\/ng.3314","journal-title":"Nat Genet"},{"key":"2946_CR36","doi-asserted-by":"publisher","first-page":"33942","DOI":"10.1074\/jbc.M111.272617","volume":"286","author":"M Nunziante","year":"2011","unstructured":"Nunziante M, Ackermann K, Dietrich K, Wolf H, G\u00e4dtke L, Gilch S et al (2011) Proteasomal dysfunction and endoplasmic reticulum stress enhance trafficking of prion protein aggregates through the secretory pathway and increase accumulation of pathologic prion protein. J Biol Chem 286:33942\u201333953. https:\/\/doi.org\/10.1074\/jbc.M111.272617","journal-title":"J Biol Chem"},{"key":"2946_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-022-00120-3","author":"D Ochoa","year":"2022","unstructured":"Ochoa D, Karim M, Ghoussaini M, Hulcoop DG, McDonagh EM, Dunham I (2022) Human genetics evidence supports two-thirds of the 2021 FDA-approved drugs. Nat Rev Drug Discov. https:\/\/doi.org\/10.1038\/d41573-022-00120-3","journal-title":"Nat Rev Drug Discov"},{"key":"2946_CR38","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1002\/mc.23129","volume":"59","author":"TC Peak","year":"2020","unstructured":"Peak TC, Panigrahi GK, Praharaj PP, Su Y, Shi L, Chyr J et al (2020) Syntaxin 6-mediated exosome secretion regulates enzalutamide resistance in prostate cancer. Mol Carcinog 59:62\u201372. https:\/\/doi.org\/10.1002\/mc.23129","journal-title":"Mol Carcinog"},{"key":"2946_CR39","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nrd4051","volume":"12","author":"RM Plenge","year":"2013","unstructured":"Plenge RM, Scolnick EM, Altshuler D (2013) Validating therapeutic targets through human genetics. Nat Rev Drug Discov 12:581\u2013594. https:\/\/doi.org\/10.1038\/nrd4051","journal-title":"Nat Rev Drug Discov"},{"key":"2946_CR40","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1523\/jneurosci.17-04-01217.1997","volume":"17","author":"Y Qi","year":"1997","unstructured":"Qi Y, Wang JK, McMillian M, Chikaraishi DM (1997) Characterization of a CNS cell line, CAD, in which morphological differentiation is initiated by serum deprivation. J Neurosci Off J Soc Neurosci 17:1217\u20131225. https:\/\/doi.org\/10.1523\/jneurosci.17-04-01217.1997","journal-title":"J Neurosci Off J Soc Neurosci"},{"key":"2946_CR41","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.131175","volume":"5","author":"GJ Raymond","year":"2019","unstructured":"Raymond GJ, Zhao HT, Race B, Raymond LD, Williams K, Swayze EE et al (2019) Antisense oligonucleotides extend survival of prion-infected mice. JCI Insight 5:e131175. https:\/\/doi.org\/10.1172\/jci.insight.131175","journal-title":"JCI Insight"},{"key":"2946_CR42","doi-asserted-by":"publisher","first-page":"8354","DOI":"10.1038\/s41467-023-43961-1","volume":"14","author":"JM Ribes","year":"2023","unstructured":"Ribes JM, Patel MP, Halim HA, Berretta A, Tooze SA, Kl\u00f6hn P-C (2023) Prion protein conversion at two distinct cellular sites precedes fibrillisation. Nat Commun 14:8354. https:\/\/doi.org\/10.1038\/s41467-023-43961-1","journal-title":"Nat Commun"},{"key":"2946_CR43","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1038\/nature09768","volume":"470","author":"MK Sandberg","year":"2011","unstructured":"Sandberg MK, Al-Doujaily H, Sharps B, Clarke AR, Collinge J (2011) Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature 470:540\u2013542. https:\/\/doi.org\/10.1038\/nature09768","journal-title":"Nature"},{"key":"2946_CR44","doi-asserted-by":"publisher","first-page":"4347","DOI":"10.1038\/ncomms5347","volume":"5","author":"MK Sandberg","year":"2014","unstructured":"Sandberg MK, Al-Doujaily H, Sharps B, De Oliveira MW, Schmidt C, Richard-Londt A et al (2014) Prion neuropathology follows the accumulation of alternate prion protein isoforms after infective titre has peaked. Nat Commun 5:4347. https:\/\/doi.org\/10.1038\/ncomms5347","journal-title":"Nat Commun"},{"key":"2946_CR45","doi-asserted-by":"publisher","unstructured":"Sangar D, Hill E, Jack K, Batchelor M, Mistry B, Ribes JM, Jackson GS, Mead S, Bieschke J (2024) Syntaxin-6 delays prion protein fibril formation and prolongs presence of toxic aggregation intermediates. eLife 13: e83320 https:\/\/doi.org\/10.7554\/eLife.83320","DOI":"10.7554\/eLife.83320"},{"issue":"12","key":"2946_CR46","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.150165","volume":"5","author":"C Schmidt","year":"2015","unstructured":"Schmidt C, Fizet J, Properzi F, Batchelor M, Sandberg MK, Edgeworth JA, Afran L, Ho S, Badhan A, Klier S et al (2015) A systematic investigation of production of synthetic prions from recombinant prion protein. Open Biol 5(12):150165. https:\/\/doi.org\/10.1098\/rsob.150165","journal-title":"Open Biol"},{"key":"2946_CR47","doi-asserted-by":"publisher","first-page":"21658","DOI":"10.1038\/srep21658","volume":"6","author":"SY Shim","year":"2016","unstructured":"Shim SY, Karri S, Law S, Schatzl HM, Gilch S (2016) Prion infection impairs lysosomal degradation capacity by interfering with rab7 membrane attachment in neuronal cells. Sci Rep 6:21658. https:\/\/doi.org\/10.1038\/srep21658","journal-title":"Sci Rep"},{"key":"2946_CR48","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1086\/381166","volume":"189","author":"I Vorberg","year":"2004","unstructured":"Vorberg I, Raines A, Story B, Priola SA (2004) Susceptibility of common fibroblast cell lines to transmissible spongiform encephalopathy agents. J Infect Dis 189:431\u2013439. https:\/\/doi.org\/10.1086\/381166","journal-title":"J Infect Dis"},{"key":"2946_CR49","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1034\/j.1600-0854.2001.20903.x","volume":"2","author":"F Wendler","year":"2001","unstructured":"Wendler F, Tooze S (2001) Syntaxin 6: the promiscuous behaviour of a SNARE protein. Traffic (Copenhagen, Denmark) 2:606\u2013611. https:\/\/doi.org\/10.1034\/j.1600-0854.2001.20903.x","journal-title":"Traffic (Copenhagen, Denmark)"},{"key":"2946_CR50","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/s41588-020-00773-z","volume":"53","author":"AP Wingo","year":"2021","unstructured":"Wingo AP, Liu Y, Gerasimov ES, Gockley J, Logsdon BA, Duong DM et al (2021) Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer\u2019s disease pathogenesis. Nat Genet 53:143\u2013146. https:\/\/doi.org\/10.1038\/s41588-020-00773-z","journal-title":"Nat Genet"}],"updated-by":[{"DOI":"10.1007\/s00401-026-03003-8","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000}}],"container-title":["Acta Neuropathologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-025-02946-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00401-025-02946-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-025-02946-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T05:31:58Z","timestamp":1774935118000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00401-025-02946-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,4]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["2946"],"URL":"https:\/\/doi.org\/10.1007\/s00401-025-02946-8","relation":{},"ISSN":["1432-0533"],"issn-type":[{"value":"1432-0533","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,4]]},"assertion":[{"value":"2 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 September 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 October 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 November 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 March 2026","order":6,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":7,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The original online version of this article was revised due to given names of the authors Mitali M. Patel and Peter-Christian Kl\u00f6hn was incorrectly published as Mitali Patel and Peter Kloehn. Now, the author names has been corrected.","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 March 2026","order":9,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":10,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":11,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1007\/s00401-026-03003-8","URL":"https:\/\/doi.org\/10.1007\/s00401-026-03003-8","order":12,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"J.C. is the director of D-Gen, Ltd., an academic spin-out company working in the field of prion disease diagnosis, decontamination, and therapeutics. J.C. and G.S.J. are shareholders of D-Gen. D-Gen supplied the ICSM35 antibody used for PrP immunohistochemistry and ICSM18 antibody used for cell experiments. The other authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"48"}}