Autophagic enhancer rescues Tau accumulation in a stem cell model of frontotemporal dementia
Year: 2024
Type: preprint
Abstract: Tau degradation is disrupted in neurodegenerative tauopathies, such as frontotemporal dementia (FTD), which may contribute to Tau aggregation. The prevailing hypothesis has been that Tau degradation is stymied due to an imbalance in proteostasis that occurs with age. Here, we used Airyscan super resolution imaging to illustrate that a pathogenic FTD mutation in the MAPT gene, which encodes Tau, is sufficient to alter multiple steps of the autophagy lysosomal pathway and impair Tau degradation. We discovered lysosomes clogged with both Tau and phosphorylated Tau, stalled lysosome motility, disrupted molecular motors, enhanced autophagic flux, and slowed cargo degradation in mutant Tau neurons. Treatment of mutant Tau neurons with a small molecule autophagy enhancer drug increases autophagic flux and cargo degradation, reduces phospho-Tau levels, and reduces Tau accumulation in lysosomes without restoring defects in lysosomal motility. This study reveals novel effects of mutant Tau and provides a window through which therapeutic treatments targeting autophagy may promote Tau homeostasis.
Institutions: Washington University in St. Louis, University of Kentucky
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4403058665