{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T13:37:55Z","timestamp":1779197875134,"version":"3.51.4"},"reference-count":158,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T00:00:00Z","timestamp":1599696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009192","name":"Alberta Innovates","doi-asserted-by":"publisher","award":["G2019000542"],"award-info":[{"award-number":["G2019000542"]}],"id":[{"id":"10.13039\/501100009192","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009192","name":"Alberta Innovates","doi-asserted-by":"publisher","award":["201600010"],"award-info":[{"award-number":["201600010"]}],"id":[{"id":"10.13039\/501100009192","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Many devastating neurodegenerative diseases are driven by the misfolding of normal proteins into a pathogenic abnormal conformation. Examples of such protein misfolding diseases include Alzheimer\u2019s disease, Parkinson\u2019s disease, Huntington\u2019s disease, amyotrophic lateral sclerosis, and prion diseases. The misfolded proteins involved in these diseases form self-templating oligomeric assemblies that recruit further correctly folded protein and induce their conversion. Over time, this leads to the formation of high molecular and mostly fibrillar aggregates that are increasingly inefficient at converting normal protein. Evidence from a multitude of in vitro models suggests that fibrils are fragmented to form new seeds, which can convert further normal protein and also spread to neighboring cells as observed in vivo. While fragmentation and seed generation were suggested as crucial steps in aggregate formation decades ago, the biological pathways involved remain largely unknown. Here, we show that mechanisms of aggregate clearance\u2014namely the mammalian Hsp70\u2013Hsp40\u2013Hsp110 tri-chaperone system, macro-autophagy, and the proteasome system\u2014may not only be protective, but also play a role in fragmentation. We further review the challenges that exist in determining the precise contribution of these mechanisms to protein misfolding diseases and suggest future directions to resolve these issues.<\/jats:p>","DOI":"10.3390\/biom10091305","type":"journal-article","created":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T22:58:01Z","timestamp":1599778681000},"page":"1305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["From Seeds to Fibrils and Back: Fragmentation as an Overlooked Step in the Propagation of Prions and Prion-Like Proteins"],"prefix":"10.3390","volume":"10","author":[{"given":"Crist\u00f3bal","family":"Marrero-Winkens","sequence":"first","affiliation":[{"name":"Department of Comparative Biology &amp; Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada"},{"name":"Calgary Prion Research Unit, University of Calgary, Calgary, AB T2N 4Z6, Canada"},{"name":"Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4Z6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charu","family":"Sankaran","sequence":"additional","affiliation":[{"name":"Department of Comparative Biology &amp; Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada"},{"name":"Calgary Prion Research Unit, University of Calgary, Calgary, AB T2N 4Z6, Canada"},{"name":"Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4Z6, Canada"},{"name":"Faculty of Science, University of British Columbia, Vancouver, BC V6T 1Z4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4972-8740","authenticated-orcid":false,"given":"Hermann","family":"Sch\u00e4tzl","sequence":"additional","affiliation":[{"name":"Department of Comparative Biology &amp; Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada"},{"name":"Calgary Prion Research Unit, University of Calgary, Calgary, AB T2N 4Z6, Canada"},{"name":"Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4Z6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/418729a","article-title":"Protein-misfolding diseases: Getting out of shape","volume":"418","author":"Dobson","year":"2002","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1038\/nature02261","article-title":"Protein folding and misfolding","volume":"426","author":"Dobson","year":"2003","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1002\/ana.24897","article-title":"The burden of neurological disease in the United States: A summary report and call to action","volume":"81","author":"Gooch","year":"2017","journal-title":"Ann. 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