{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:17:08Z","timestamp":1789193828215,"version":"build-2803163510"},"posted":{"date-parts":[[2026,5,14]]},"group-title":"Biophysics","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["(Career Development Award 847236)"],"award-info":[{"award-number":["(Career Development Award 847236)"]}],"id":[{"id":"https:\/\/ror.org\/013kjyp64","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Institutes of Health, National Heart, Lung, and Blood Institute","award":["(New Innovator Award DP2-HL163810)"],"award-info":[{"award-number":["(New Innovator Award DP2-HL163810)"]}]},{"name":"National Institutes of Health, National Heart, Lung, and Blood Institute","award":["R01HL177670"],"award-info":[{"award-number":["R01HL177670"]}]},{"name":"UTSW Endowment","award":["(Distinguished Researcher Award from President\u2019s Research Council and start-up funds)"],"award-info":[{"award-number":["(Distinguished Researcher Award from President\u2019s Research Council and start-up funds)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Amyloid deposition in the central nervous system is increasingly recognized in transthyretin (ATTR) amyloidosis, particularly in patients with prolonged survival following liver transplantation or disease-modifying therapies. However, the structural basis of transthyretin aggregation in the brain remains unknown. Here we determine cryo-electron microscopy (cryo-EM) structures of\n                  <jats:italic>ex vivo<\/jats:italic>\n                  brain-derived ATTR fibrils from patients carrying the ATTRv-V30M and ATTRv-V30G variants. Both fibrils adopt folds distinct from those previously reported in peripheral tissues and the vitreous humor. V30M fibrils exhibit a continuous ordered core spanning residues Pro11\u2013Asn124, whereas V30G fibrils consist of a substantially reduced ordered core, revealing pronounced structural divergence even within the same tissue environment. Despite this diversity, comparative analyses identify conserved regions across ATTR fibrils, including a segment implicated in transthyretin aggregation and targeted for diagnostic and therapeutic development. These results provide direct evidence that local tissue context can shape amyloid fibril architecture in human disease.\n                <\/jats:p>","DOI":"10.64898\/2026.05.12.724695","type":"posted-content","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T13:00:45Z","timestamp":1778763645000},"source":"Crossref","is-referenced-by-count":1,"title":["Transthyretin amyloid fibrils adopt distinct folds in the brain"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8671-1617","authenticated-orcid":false,"given":"Shumaila","family":"Afrin","sequence":"first","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Department of Biophysics, Peter O\u2019Donnell Jr Brain Institute, University of Texas Southwestern Medical Center (UTSW), Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7055-8809","authenticated-orcid":false,"given":"Binh An","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Department of Biophysics, Peter O\u2019Donnell Jr Brain Institute, University of Texas Southwestern Medical Center (UTSW), Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5162-7212","authenticated-orcid":false,"given":"Parker","family":"Bassett","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Department of Biophysics, Peter O\u2019Donnell Jr Brain Institute, University of Texas Southwestern Medical Center (UTSW), Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3265-5242","authenticated-orcid":false,"given":"Maria","family":"del Carmen Fernandez-Ramirez","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Department of Biophysics, Peter O\u2019Donnell Jr Brain Institute, University of Texas Southwestern Medical Center (UTSW), Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6354-3588","authenticated-orcid":false,"given":"Rose","family":"Pedretti","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Department of Biophysics, Peter O\u2019Donnell Jr Brain Institute, University of Texas Southwestern Medical Center (UTSW), Dallas, TX, USA"},{"name":"AmyGo Solutions, Inc., Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Layla","family":"Villalon","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Department of Biophysics, Peter O\u2019Donnell Jr Brain Institute, University of Texas Southwestern Medical Center (UTSW), Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candace","family":"Kelly","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Department of Biophysics, Peter O\u2019Donnell Jr Brain Institute, University of Texas Southwestern Medical Center (UTSW), Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center (UTSW), Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihir","family":"Madabushi","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Department of Biophysics, Peter O\u2019Donnell Jr Brain Institute, University of Texas Southwestern Medical Center (UTSW), Dallas, TX, 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