Disruption of sphingolipid metabolism promotes tau seeding through endolysosomal membrane rigidification and rupture
Abstract
Endolysosomal dysfunction is a hallmark of Alzheimer’s disease and related tauopathies, yet underlying mechanisms remain poorly understood. This study investigates the role of sphingolipid metabolism in maintaining endolysosomal membrane integrity and its impact on tau aggregation and toxicity in Caenorhabditis elegans and human cell culture models. Fluorescence recovery after photobleaching and C-Laurdan dye imaging revealed that silencing sphingolipid metabolism genes reduced endolysosomal vesicle membrane fluidity, increasing their rupture. The accumulation of aggregated tau in endolysosomal vesicles further aggravated endomembrane rigidification and damage, and promoted seeded tau aggregation, potentially by facilitating the escape of tau seeds from the endolysosomal system. Supplementation with unsaturated fatty acids improved membrane fluidity, suppressing endolysosomal rupture and seeded tau aggregation in cell models, and alleviating tau-associated neurotoxicity in C. elegans. Together, this study provides mechanistic insight into how perturbation of sphingolipid metabolism promotes endolysosomal membrane damage and contributes to the escape of aggregated tau from this compartment, suggesting that restoration of membrane fluidity may represent a strategy to limit tau propagation and toxicity.
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BibTeX
@article{tittelmeier2026disruption,
title = {{Disruption of sphingolipid metabolism promotes tau seeding through endolysosomal membrane rigidification and rupture}},
author = {Jessica Tittelmeier and Carl Alexander Sandhof and Nicole Martin and Deike El-Kabarity and Soki Bradel Ngonza-Nito and Ronald Melki and Carmen Nussbaum-Krammer},
journal = {eLife},
year = {2026},
month = aug,
doi = {10.7554/elife.106865},
url = {https://cnrs.hal.science/hal-05758482v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Disruption of sphingolipid metabolism promotes tau seeding through endolysosomal membrane rigidification and rupture
AU - Jessica Tittelmeier
AU - Carl Alexander Sandhof
AU - Nicole Martin
AU - Deike El-Kabarity
AU - Soki Bradel Ngonza-Nito
AU - Ronald Melki
AU - Carmen Nussbaum-Krammer
PY - 2026
DA - 2026/08/27
JO - eLife
DO - 10.7554/elife.106865
UR - https://cnrs.hal.science/hal-05758482v1
AB - Endolysosomal dysfunction is a hallmark of Alzheimer’s disease and related tauopathies, yet underlying mechanisms remain poorly understood. This study investigates the role of sphingolipid metabolism in maintaining endolysosomal membrane integrity and its impact on tau aggregation and toxicity in Caenorhabditis elegans and human cell culture models. Fluorescence recovery after photobleaching and C-Laurdan dye imaging revealed that silencing sphingolipid metabolism genes reduced endolysosomal vesicle membrane fluidity, increasing their rupture. The accumulation of aggregated tau in endolysosomal vesicles further aggravated endomembrane rigidification and damage, and promoted seeded tau aggregation, potentially by facilitating the escape of tau seeds from the endolysosomal system. Supplementation with unsaturated fatty acids improved membrane fluidity, suppressing endolysosomal rupture and seeded tau aggregation in cell models, and alleviating tau-associated neurotoxicity in C. elegans. Together, this study provides mechanistic insight into how perturbation of sphingolipid metabolism promotes endolysosomal membrane damage and contributes to the escape of aggregated tau from this compartment, suggesting that restoration of membrane fluidity may represent a strategy to limit tau propagation and toxicity.
SN - 2050-084X
ER -