{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T23:23:59Z","timestamp":1793316239595,"version":"4.5.0"},"posted":{"date-parts":[[2026,6,10]]},"group-title":"Cell Biology","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["ASAP-000350"],"award-info":[{"award-number":["ASAP-000350"]}],"id":[{"id":"https:\/\/ror.org\/03zj4c476","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The prion-like spread of tau from cell to cell in the central nervous system involves escape from the endolysosomal network, which is counteracted by the lysosomal repair activity of the ESCRT system. Here, we investigate whether other components of the lysosomal damage sensing and repair system, namely the ESCRT-recruiting Ca\n                  <jats:sup>2+<\/jats:sup>\n                  sensor ALG-2, conjugation of ATG8s to single membranes (CASM), the phosphoinositide-initiated tethering and lipid transport (PITT) pathway, and the Parkinson\u2019s disease-related lipid transporter VPS13C are involved in tau spread. We found that the PITT pathway and VPS13C are strongly implicated in tau seeding by pre-formed fibrils (PFFs) in both neurons and astrocytes, CASM has a major role in astrocytes but not neurons, and ALG-2 has a lesser role in both. We then investigated the mechanism of damage and seeding by tau PFFs using cryo-electron tomography. Unlike the classical lysosome damage agent LLOMe, tau PFFs were not seen to directly interact with the lysosomal membrane, nor do they distort local membrane curvature. Lysosomes in PFF-treated cells were structurally intact. Extensive protein aggregates of similar character were seen in both the lysosomal lumen and in the cytosol proximal to lysosomes. The observations are consistent with the PFF-induced co-aggregation of tau with other cellular materials within lysosomes, with leakage to the cytosol attributed to reversible holes in the lysosome membrane.\n                <\/jats:p>","DOI":"10.64898\/2026.06.08.731026","type":"posted-content","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T10:00:19Z","timestamp":1781085619000},"source":"Crossref","is-referenced-by-count":1,"title":["Structural Mechanism and Cellular Restriction of Tau Seeding from Endolysosomes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0499-0083","authenticated-orcid":false,"given":"Eric","family":"Herrmann","sequence":"first","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA"},{"name":"California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA"},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuixia","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA"},{"name":"California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9373-4147","authenticated-orcid":false,"given":"Kevin M.","family":"Rose","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA"},{"name":"California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8917-0249","authenticated-orcid":false,"given":"Richard M.","family":"Hooy","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA"},{"name":"California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5054-5445","authenticated-orcid":false,"given":"James H.","family":"Hurley","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA"},{"name":"California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA"},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA"},{"name":"Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061311201457000_2026.06.08.731026v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-030222-102505"},{"key":"2026061311201457000_2026.06.08.731026v1.2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41580-025-00873-w","article-title":"Lysosomal membrane homeostasis and its importance in physiology and disease","volume":"27","year":"2026","journal-title":"Nat. Rev. Mol. Cell Biol"},{"key":"2026061311201457000_2026.06.08.731026v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-024-02799-7"},{"key":"2026061311201457000_2026.06.08.731026v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2025.102482"},{"key":"2026061311201457000_2026.06.08.731026v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nature20416"},{"key":"2026061311201457000_2026.06.08.731026v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1901"},{"key":"2026061311201457000_2026.06.08.731026v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2010.04.003"},{"key":"2026061311201457000_2026.06.08.731026v1.8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M808759200"},{"key":"2026061311201457000_2026.06.08.731026v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2021.12.004"},{"key":"2026061311201457000_2026.06.08.731026v1.10","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-061516-045049"},{"key":"2026061311201457000_2026.06.08.731026v1.11","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar5078"},{"key":"2026061311201457000_2026.06.08.731026v1.12","doi-asserted-by":"crossref","unstructured":"Radulovic, M. et al. ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival. EMBO J. 37, EMBJ201899753 (2018).","DOI":"10.15252\/embj.201899753"},{"key":"2026061311201457000_2026.06.08.731026v1.13","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.009432"},{"key":"2026061311201457000_2026.06.08.731026v1.14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2315690121"},{"key":"2026061311201457000_2026.06.08.731026v1.15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2205590119"},{"key":"2026061311201457000_2026.06.08.731026v1.16","doi-asserted-by":"crossref","first-page":"e202303078","DOI":"10.1083\/jcb.202303078","article-title":"Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy","volume":"222","year":"2023","journal-title":"J. Cell Biol"},{"key":"2026061311201457000_2026.06.08.731026v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/S41556-025-01653-6"},{"key":"2026061311201457000_2026.06.08.731026v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05164-4"},{"key":"2026061311201457000_2026.06.08.731026v1.19","doi-asserted-by":"crossref","unstructured":"Boyle, K. B. et al. TECPR1 conjugates LC3 to damaged endomembranes upon detection of sphingomyelin exposure. EMBO J. 42, EMBJ2022113012 (2023).","DOI":"10.15252\/embj.2022113012"},{"key":"2026061311201457000_2026.06.08.731026v1.20","doi-asserted-by":"crossref","unstructured":"Corkery, D. P. , Castro-Gonzalez, S. , Knyazeva, A. , Herzog, L. K. & Wu, Y . An ATG12-ATG5-TECPR1 E3-like complex regulates unconventional LC3 lipidation at damaged lysosomes. EMBO Rep. 24, EMBR202356841 (2023).","DOI":"10.15252\/embr.202356841"},{"key":"2026061311201457000_2026.06.08.731026v1.21","first-page":"e113105","article-title":"TECPR1 is activated by damage-induced sphingomyelin exposure to mediate noncanonical autophagy","volume":"42","year":"2023","journal-title":"EMBO J"},{"key":"2026061311201457000_2026.06.08.731026v1.22","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022112677"},{"key":"2026061311201457000_2026.06.08.731026v1.23","first-page":"159003","article-title":"Insights into VPS13 properties and function reveal a new mechanism of eukaryotic lipid transport","volume":"1866","year":"2021","journal-title":"Biochim. Biophys. Acta BBA - Mol. Cell Biol. Lipids"},{"key":"2026061311201457000_2026.06.08.731026v1.24","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201811139"},{"key":"2026061311201457000_2026.06.08.731026v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-019-0203-4"},{"key":"2026061311201457000_2026.06.08.731026v1.26","doi-asserted-by":"crossref","first-page":"11406","DOI":"10.1523\/JNEUROSCI.1230-17.2017","article-title":"Pathological Tau Strains from Human Brains Recapitulate the Diversity of Tauopathies in Nontransgenic Mouse Brain","volume":"37","year":"2017","journal-title":"J. Neurosci. OD. J. Soc. Neurosci"},{"key":"2026061311201457000_2026.06.08.731026v1.27","doi-asserted-by":"publisher","DOI":"10.1201\/9780429258770"},{"key":"2026061311201457000_2026.06.08.731026v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3810"},{"key":"2026061311201457000_2026.06.08.731026v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.022"},{"key":"2026061311201457000_2026.06.08.731026v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7696(08)60527-6"},{"key":"2026061311201457000_2026.06.08.731026v1.31","doi-asserted-by":"publisher","DOI":"10.64898\/2026.01.17.700056"},{"key":"2026061311201457000_2026.06.08.731026v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2024.07.003"},{"key":"2026061311201457000_2026.06.08.731026v1.33","doi-asserted-by":"publisher","DOI":"10.1101\/2025.09.07.674666"},{"key":"2026061311201457000_2026.06.08.731026v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.01.014"},{"key":"2026061311201457000_2026.06.08.731026v1.35","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1147-9"},{"key":"2026061311201457000_2026.06.08.731026v1.36","doi-asserted-by":"crossref","first-page":"e202304042","DOI":"10.1083\/jcb.202304042","article-title":"VPS13C regulates phospho-Rab10-mediated lysosomal function in human dopaminergic neurons","volume":"223","year":"2024","journal-title":"J. Cell Biol"},{"key":"2026061311201457000_2026.06.08.731026v1.37","doi-asserted-by":"publisher","DOI":"10.64898\/2025.12.23.696283"},{"key":"2026061311201457000_2026.06.08.731026v1.38","doi-asserted-by":"publisher","DOI":"10.64898\/2026.03.26.714634"},{"key":"2026061311201457000_2026.06.08.731026v1.39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.26.15712"},{"key":"2026061311201457000_2026.06.08.731026v1.40","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1411649111"},{"key":"2026061311201457000_2026.06.08.731026v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2020.05.011"},{"key":"2026061311201457000_2026.06.08.731026v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/nature23002"},{"key":"2026061311201457000_2026.06.08.731026v1.43","doi-asserted-by":"crossref","unstructured":"Zhang, W. et al. Heparin-induced tau filaments are polymorphic and dijer from those in Alzheimer\u2019s and Pick\u2019s diseases. eLife 8, e43584.","DOI":"10.7554\/eLife.43584"},{"key":"2026061311201457000_2026.06.08.731026v1.44","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1021\/acschemneuro.0c00469","article-title":"Extensive Plasmid Library to Prepare Tau Protein Variants and Study Their Functional Biochemistry","volume":"11","year":"2020","journal-title":"ACS Chem. Neurosci"},{"key":"2026061311201457000_2026.06.08.731026v1.45","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.73.011303.074112"},{"key":"2026061311201457000_2026.06.08.731026v1.46","first-page":"e202401136","article-title":"Neuronal constitutive endolysosomal perforations enable \u03b1-synuclein aggregation by internalized PFFs","volume":"224","year":"2024","journal-title":"J. Cell Biol"},{"key":"2026061311201457000_2026.06.08.731026v1.47","doi-asserted-by":"publisher","DOI":"10.1101\/2025.11.02.686178"},{"key":"2026061311201457000_2026.06.08.731026v1.48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2318412121"},{"key":"2026061311201457000_2026.06.08.731026v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.07.014"},{"key":"2026061311201457000_2026.06.08.731026v1.50","doi-asserted-by":"publisher","DOI":"10.1038\/s44318-025-00436-x"},{"key":"2026061311201457000_2026.06.08.731026v1.51","doi-asserted-by":"publisher","DOI":"10.1002\/cpcb.51"},{"key":"2026061311201457000_2026.06.08.731026v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-022-01690-1"},{"key":"2026061311201457000_2026.06.08.731026v1.53","doi-asserted-by":"publisher","DOI":"10.17504\/protocols.io.yxmvm8149g3p\/v1"},{"key":"2026061311201457000_2026.06.08.731026v1.54","doi-asserted-by":"publisher","DOI":"10.1017\/S2633903X23000132"},{"key":"2026061311201457000_2026.06.08.731026v1.55","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4193"},{"key":"2026061311201457000_2026.06.08.731026v1.56","first-page":"100068","article-title":"AreTomo: An integrated software package for automated marker-free, motion-corrected cryo-electron tomographic alignment and reconstruction","volume":"6","year":"2022","journal-title":"J. Struct. Biol. X"},{"key":"2026061311201457000_2026.06.08.731026v1.57","doi-asserted-by":"publisher","DOI":"10.64898\/2025.12.09.693325"},{"key":"2026061311201457000_2026.06.08.731026v1.58","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq692"},{"key":"2026061311201457000_2026.06.08.731026v1.59","doi-asserted-by":"publisher","DOI":"10.1101\/2024.01.05.574336"},{"key":"2026061311201457000_2026.06.08.731026v1.60","doi-asserted-by":"publisher","DOI":"10.1006\/jsbi.1996.0013"},{"key":"2026061311201457000_2026.06.08.731026v1.61","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3943"},{"key":"2026061311201457000_2026.06.08.731026v1.62","first-page":"e202505059","article-title":"Surface Morphometrics reveals local membrane thickness variation in organellar subcompartments","volume":"225","year":"2025","journal-title":"J. Cell Biol"},{"key":"2026061311201457000_2026.06.08.731026v1.63","doi-asserted-by":"publisher","DOI":"10.1110\/ps.04688204"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.08.731026","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T18:20:27Z","timestamp":1781374827000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.08.731026"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,10]]},"references-count":63,"URL":"https:\/\/doi.org\/10.64898\/2026.06.08.731026","relation":{},"subject":[],"published":{"date-parts":[[2026,6,10]]},"subtype":"preprint"}}