{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:24:20Z","timestamp":1792650260014,"version":"4.5.0"},"reference-count":78,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T00:00:00Z","timestamp":1650499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021730","name":"Alberta Prion Research Institute","doi-asserted-by":"publisher","award":["201700013"],"award-info":[{"award-number":["201700013"]}],"id":[{"id":"10.13039\/501100021730","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institues of Health","doi-asserted-by":"crossref","award":["2R01AI112956-06"],"award-info":[{"award-number":["2R01AI112956-06"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The metazoan Hsp70 disaggregase protects neurons from proteotoxicity that arises from the accumulation of misfolded protein aggregates. Hsp70 and its co-chaperones disassemble and extract polypeptides from protein aggregates for refolding or degradation. The effectiveness of the chaperone system decreases with age and leads to accumulation rather than removal of neurotoxic protein aggregates. Therapeutic enhancement of the Hsp70 protein disassembly machinery is proposed to counter late-onset protein misfolding neurodegenerative disease that may arise. In the context of prion disease, it is not known whether stimulation of protein aggregate disassembly paradoxically leads to enhanced formation of seeding competent species of disease-specific proteins and acceleration of neurodegenerative disease. Here we have tested the hypothesis that modulation of Hsp70 disaggregase activity perturbs mammalian prion-induced neurotoxicity and prion seeding activity. To do so we used prion protein (PrP) transgenic Drosophila that authentically replicate mammalian prions. RNASeq identified that Hsp70, DnaJ-1 and Hsp110 gene expression was downregulated in prion-exposed PrP Drosophila. We demonstrated that RNAi knockdown of Hsp110 or DnaJ-1 gene expression in variant Creutzfeldt\u2013Jakob disease prion-exposed human PrP Drosophila enhanced neurotoxicity, whereas overexpression mitigated toxicity. Strikingly, prion seeding activity in variant Creutzfeldt\u2013Jakob disease prion-exposed human PrP Drosophila was ablated or reduced by Hsp110 or DnaJ-1 overexpression, respectively. Similar effects were seen in scrapie prion-exposed ovine PrP Drosophila with modified Hsp110 or DnaJ-1 gene expression. These unique observations show that the metazoan Hsp70 disaggregase facilitates the clearance of mammalian prions and that its enhanced activity is a potential therapeutic strategy for human prion disease.<\/jats:p>","DOI":"10.1093\/brain\/awac144","type":"journal-article","created":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T19:16:19Z","timestamp":1650482179000},"page":"3236-3249","source":"Crossref","is-referenced-by-count":17,"title":["Clearance of variant Creutzfeldt\u2013Jakob disease prions <i>in vivo<\/i> by the Hsp70 disaggregase system"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2752-1127","authenticated-orcid":false,"given":"Alana M","family":"Thackray","sequence":"first","affiliation":[{"name":"Department of Veterinary Medicine, University of Cambridge , Cambridge CB3 0ES , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3638-9025","authenticated-orcid":false,"given":"Brian","family":"Lam","sequence":"additional","affiliation":[{"name":"Medical Research Council Metabolic Diseases Unit, Wellcome\u2013MRC Institute of Metabolic Science\u2013Metabolic Research Laboratories, University of Cambridge , Cambridge CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin E","family":"McNulty","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, CO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy V","family":"Nalls","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, CO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candace K","family":"Mathiason","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, CO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srivathsa Subramanya","family":"Magadi","sequence":"additional","affiliation":[{"name":"Wallenberg Center for Molecular Medicine, Department of Clinical and Experimental Medicine, Link\u00f6ping University , 581 83 Link\u00f6ping , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walker S","family":"Jackson","sequence":"additional","affiliation":[{"name":"Wallenberg Center for Molecular Medicine, Department of Clinical and Experimental Medicine, Link\u00f6ping University , 581 83 Link\u00f6ping , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Andr\u00e9oletti","sequence":"additional","affiliation":[{"name":"UMR INRA ENVT 1225 -H\u00f4tes-Agents Pathog\u00e8nes, Ecole Nationale V\u00e9t\u00e9rinaire de Toulouse , 31076 Toulouse , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crist\u00f3bal","family":"Marrero-Winkens","sequence":"additional","affiliation":[{"name":"Calgary Prion Research Unit, Faculty of Veterinary Medicine, University of Calgary, TRW 2D10 , Calgary, AB , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann","family":"Sch\u00e4tzl","sequence":"additional","affiliation":[{"name":"Calgary Prion Research Unit, Faculty of Veterinary Medicine, University of Calgary, TRW 2D10 , Calgary, AB , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5920-4556","authenticated-orcid":false,"given":"Raymond","family":"Bujdoso","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, University of Cambridge , Cambridge CB3 0ES , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,21]]},"reference":[{"key":"2022091416374205100_awac144-B1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nature20415","article-title":"Mammalian prions and their wider relevance in neurodegenerative diseases","volume":"539","author":"Collinge","year":"2016","journal-title":"Nature"},{"key":"2022091416374205100_awac144-B2","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/s41576-018-0011-4","article-title":"Prions, prionoids and protein misfolding disorders","volume":"19","author":"Scheckel","year":"2018","journal-title":"Nat Rev Genet"},{"key":"2022091416374205100_awac144-B3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev-biochem-061516-045115","article-title":"Protein misfolding, amyloid formation, and human disease: A summary of progress over the last 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