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Tau hyperphosphorylation is linked to neurodegeneration in tauopathies, including Alzheimer\u2019s disease. Tau binds microtubules cooperatively to form cohesive envelopes, which are thought to control access to the microtubule lattice and regulate the activity of motor proteins and other MAPs. However, how disease-related perturbations affect tau dynamics and its function as a selective barrier to intracellular transport remains unclear. Using tau phospho-variants in vitro and in live neurons, we show that tau hyperphosphorylation disrupts cooperative microtubule binding and dysregulates lysosome transport. Hyperphosphorylated tau does not form envelopes, distributes more uniformly along the axon, and dissociates faster from microtubules. Tau weakly inhibits KIF5C motility, but strongly inhibits KIF1A. Hyperphosphorylation reduces KIF5C inhibition but increases KIF1A inhibition by decreasing processivity and accelerating detachment. Consistent with these effects, hyperphosphorylated tau alters lysosome transport in neurons. While phospho-resistant tau inhibits processive lysosome motility, hyperphosphorylated tau weakens tau-mediated regulation of lysosome transport, mimicking tau knockout neurons that exhibit enhanced processivity. Altogether, these findings show that hyperphosphorylation disrupts tau envelopes and impairs lysosome trafficking, likely contributing to early defects in degradative pathways that drive neurodegeneration.<\/jats:p>","DOI":"10.7554\/elife.110011","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T14:30:40Z","timestamp":1771943440000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.110011","source":"Crossref","is-referenced-by-count":0,"title":["Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons"],"prefix":"10.7554","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5955-3721","authenticated-orcid":true,"given":"Daniel","family":"Beaudet","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01pxwe438","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Bioengineering, McGill University","place":["Montreal, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Christopher L","family":"Berger","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Physiology and Biophysics, University of Vermont","place":["Burlington, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3635-1577","authenticated-orcid":true,"given":"Adam G","family":"Hendricks","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01pxwe438","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Bioengineering, McGill University","place":["Montreal, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1523\/JNEUROSCI.13-02-00856.1993","type":"journal-article","article-title":"Regional differences in microtubule dynamics in the axon","volume":"13","author":"Ahmad","year":"1993","journal-title":"The Journal of Neuroscience"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"10626","DOI":"10.1021\/bi00158a027","type":"journal-article","article-title":"Structure and novel exons of the human tau gene","volume":"31","author":"Andreadis","year":"1992","journal-title":"Biochemistry"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1016\/j.bpj.2019.01.036","type":"journal-article","article-title":"Motor dynamics underlying cargo transport by pairs of kinesin-1 and kinesin-3 motors","volume":"116","author":"Arpa\u011f","year":"2019","journal-title":"Biophysical Journal"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1002\/jnr.490300115","type":"journal-article","article-title":"Microtubule dynamics in axons and dendrites","volume":"30","author":"Baas","year":"1991","journal-title":"Journal of Neuroscience Research"},{"key":"bib5","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E22-01-0018","type":"journal-article","article-title":"Tau differentially regulates the transport of early endosomes and lysosomes","volume":"33","author":"Balabanian","year":"2022","journal-title":"Molecular Biology of the Cell"},{"key":"bib6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107323","type":"journal-article","article-title":"The types and numbers of kinesins and dyneins transporting endocytic cargoes modulate their motility and response to tau","volume":"300","author":"Beaudet","year":"2024","journal-title":"The Journal of Biological Chemistry"},{"key":"bib7","type":"software","article-title":"Scripts_data_Beaudet_Berger_Hendricks_eLife_2026","volume-title":"Software Heritage","author":"Beaudet","year":"2026","unstructured":"Beaudet D. 2026. 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