Galectin-8-mediated selective autophagy protects against seeded tau aggregation

Area of Science:

• Neurobiology
• Cellular Biology
• Neurodegenerative Diseases

Background:

• Assembled tau proteins propagate between cells, seeding further aggregation and contributing to neurodegenerative diseases like Alzheimer's.
• Understanding how tau seeds enter cells and trigger cellular responses is crucial for developing therapeutic strategies.

Purpose of the Study:

• To investigate the mechanisms by which assembled tau seeds enter the cell cytosol.
• To determine if cellular entry of tau seeds activates protective cellular defenses.

Main Methods:

• Investigated tau entry via clathrin-independent endocytosis.
• Examined endomembrane damage detection by galectin-8.
• Assessed autophagy activation via nuclear dot protein 52 (NDP52) and p62.
• Inhibited galectin-8 and NDP52 to observe effects on tau aggregation.

Main Results:

• Tau assemblies enter cells through clathrin-independent endocytosis and escape into the cytosol.
• Galectin-8 detects damaged endomembranes, activating NDP52-mediated autophagy.
• Inhibiting this autophagy pathway enhanced seeded tau aggregation.
• p62 targeted seeded tau aggregates within the cytosol.

Conclusions:

• Cellular defenses, particularly galectin-8 and NDP52-dependent autophagy, protect against tau seed entry and aggregation.
• Autophagy activation upon detecting endomembrane damage acts as a defense against cytosolic tau seeds.
• These findings offer insights into therapeutic approaches for neurodegenerative diseases by targeting protein aggregate propagation.