Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons.
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Overview
- Department of Bioengineering, McGill University, Montreal, Canada
- Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, United States
Abstract
Tau, a neuronal microtubule-associated protein (MAP), organizes the axonal cytoskeleton, and regulates intracellular transport. Tau hyperphosphorylation is linked to neurodegeneration in tauopathies, including Alzheimer’s 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.
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danielbeaudet-McGill/scripts_data_Beaudet_Berger_Hendricks_eLife_2026
f93747b8e76a805e1e3686a2277ce91ec6986386, 15 September 2026Availability: 1 check, the latest on 29 September 2026: the link answers
- 29 September 2026: the link answers
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- LICENSE, License, 21 lines
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Cite
This paper
Beaudet, D., Berger, C. L., & Hendricks, A. G. (2026). Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons. eLife, 15, RP110011. https://
BibTeX
@article{beaudet2026tau,
author = {Beaudet, Daniel and Berger, Christopher L and Hendricks, Adam G},
title = {{Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons}},
journal = {eLife},
year = {2026},
month = sep,
volume = {15},
pages = {RP110011},
publisher = {eLife Sciences Publications, Ltd},
issn = {2050-084X},
doi = {10.7554/
url = {https://
pmid = {42804373},
pmcid = {PMC13619133}
}
RIS
TY - JOUR
AU - Beaudet, Daniel
AU - Berger, Christopher L
AU - Hendricks, Adam G
TI - Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons
T2 - eLife
J2 - eLife
PY - 2026
DA - 2026/
VL - 15
SP - RP110011
SN - 2050-084X
PB - eLife Sciences Publications, Ltd
DO - 10.7554/
UR - https://
LA - en
ER -
CSL-JSON
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