Abstract
Assembled tau can transfer between cells and seed the aggregation of soluble tau. This process is thought to underlie the amplification and propagation of tau inclusions throughout the brain in neurodegenerative diseases, including Alzheimer's disease. An understanding of the mechanisms involved may provide strategies for limiting assembled tau propagation. Here, we sought to determine how assembled tau seeds gain access to the cytosol and whether this access triggers cellular defenses. We show that tau assemblies enter cells through clathrin-independent endocytosis and escape from damaged endomembranes into the cytosol, where they seed the aggregation of soluble tau. We also found that the danger receptor galectin-8 detects damaged endomembranes and activates autophagy through recruitment of the cargo receptor nuclear dot protein 52 (NDP52). Inhibition of galectin-8– and NDP52-dependent autophagy increased seeded tau aggregation, indicating that autophagy triggered by damaged endomembranes during the entry of assembled tau seeds protects against tau aggregation, in a manner similar to cellular defenses against cytosol-dwelling microorganisms. A second autophagy cargo receptor, p62, then targeted seeded tau aggregates. Our results reveal that by monitoring endomembrane integrity, cells reduce entry of tau seeds into the cytosol and thereby prevent seeded aggregation. The mechanisms described here may help inform the development of therapies aimed at inhibiting the propagation of protein assemblies in neurodegenerative diseases.
Highlights
Assembled tau can transfer between cells and seed the aggregation of soluble tau
We found that the danger receptor galectin-8 detects damaged endomembranes and activates autophagy through recruitment of the cargo receptor nuclear dot protein 52 (NDP52)
To investigate if assembled tau seeds escape from the endo-lysosomal system and to study downstream effects, we looked at the roles of galectin-8, NDP52, p62, and optineurin
Summary
Clathrin-independent endocytosis of tau seeds is required for seeded tau aggregation. To investigate if galectin-8 recruitment to tau seed– containing vesicles restricts seeded aggregation of cytosolic tau, we depleted galectin-8 in HeLa cells expressing P301S tau. We investigated the targeting of fluorescently labeled assembled tau seeds by these autophagy cargo receptors following uptake in HeLa cells and, subsequently, the targeting of seeded tau aggregates formed after 48 h of growth. To investigate whether targeting by autophagy cargo receptors restricts seeded tau aggregation, we used siRNAs to deplete NDP52, p62, and optineurin in HeLa cells expressing P301S tau. We conclude that NDP52 restricts seeded tau aggregation in a galectin-8 – dependent, ubiquitinindependent manner by diverting tau seeds to autophagy, revealing that by monitoring the integrity of endomembranes, cells protect their cytosol against the entry of tau seeds
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