A disease-causing MAPT p.R406W Tau mutation disrupted neuronal -lysosome clearance and limited Tau degradation.
Evidence
This human-neuron model used super-resolution imaging and pharmacologic autophagy enhancement to track Tau, lysosome function, cargo clearance, and Tau levels.
Caveat
The findings come from a cellular disease model, and boosting autophagy lowered Tau without restoring lysosomal motility defects.
Simplified
Tau accumulates in a group of neurodegenerative diseases known as . A prevailing hypothesis has been that Tau degradation is impaired due to an age-related imbalance in the -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.
Key numbers
67.1%
Increase in lysosomes free of Tau
Percentage of lysosomes free of Tau in G2-567 treated p.R406W neurons.
37
Decrease in total Tau levels
Mean intensity of total Tau per cell in G2-567 treated p.R406W neurons.
56
Decrease in pTau levels
Mean intensity of pTau per cell in G2-567 treated p.R406W neurons.
Full Text
We can’t show the full text here under this license.
