2026-03-31 ワシントン大学セントルイス校
Researchers at WashU Medicine have shown that a novel compound they developed can clear a harmful protein from human neurons modeling frontotemporal dementia (shown) and prevent those neurons from dying. (Image: Farzane Mirfakhar)
＜関連情報＞
- https://source.washu.edu/2026/03/chemical-compound-clears-cellular-waste-protects-neurons-in-model-of-frontotemporal-dementia/
- https://medicine.washu.edu/news/chemical-compound-clears-cellular-waste-protects-neurons-in-model-of-frontotemporal-dementia/
- https://www.nature.com/articles/s41467-026-70473-5
病原性タウ変異は、前頭側頭型認知症モデルにおいて、タウ分解を制限するオートファジー・リソソーム機能不全を引き起こす A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia
Farzaneh S. Mirfakhar,Jacob A. Marsh,Chihiro Sato,Kylie J. Schache,Miguel A. Minaya,Roland E. Dolle,Stephen C. Pak,Gary A. Silverman,David H. Perlmutter,Shannon L. Macauley & Celeste M. Karch
Nature Communications Published:31 March 2026
DOI:https://doi.org/10.1038/s41467-026-70473-5
Abstract
Tau accumulates in a group of neurodegenerative diseases known as tauopathies. A prevailing hypothesis has been that Tau degradation is impaired due to an age-related imbalance in the autophagy-lysosome pathway, but whether these defects are a cause or consequence of Tau accumulation remains unclear. Here we show that a disease-causing mutation in the MAPT gene, which encodes Tau, p.R406W, is sufficient to disrupt multiple steps of the autophagy-lysosome pathway in human neurons. Using Airyscan super-resolution imaging, we find that mutant Tau neurons accumulate Tau and phosphorylated Tau in dysfunctional lysosomes, exhibit reduced lysosome motility, impaired fusion of autophagosomes and lysosomes, and increased undegraded cellular cargo. Pharmacological enhancement of autophagy improves cargo clearance and lowers Tau levels, without restoring defects in lysosomal motility. Together, these findings demonstrate that mutant Tau directly perturbs cellular clearance pathways and suggest that boosting autophagy may help restore Tau homeostasis in tauopathies.
