Structural Mechanism and Cellular Restriction of Tau Seeding from Endolysosomes

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Prion-like tau spread is crucial for central nervous system diseases.
• The ESCRT system repairs endolysosomal damage, counteracting tau spread.
• Lysosomal damage sensing and repair pathways are potential regulators of tau propagation.

Purpose of the Study:

• To investigate the role of ALG-2, CASM, PITT pathway, and VPS13C in tau spread.
• To elucidate the mechanism of lysosomal damage and seeding by tau pre-formed fibrils (PFFs).

Main Methods:

• Cellular assays in neurons and astrocytes.
• Investigation of tau seeding by PFFs.
• Cryo-electron tomography to visualize cellular structures and PFF interactions.

Main Results:

• The PITT pathway and VPS13C significantly contribute to tau seeding in both neurons and astrocytes.
• Conjugation of ATG8s to single membranes (CASM) plays a major role in astrocytes but not neurons.
• ALG-2 shows a lesser role in tau spread in both cell types.
• Tau PFFs induce lysosomal damage through co-aggregation within lysosomes, leading to reversible cytosolic leakage, rather than direct membrane interaction.

Conclusions:

• The PITT pathway and VPS13C are critical components in the cellular spread of tau pathology.
• Tau PFFs cause lysosomal dysfunction via intracellular co-aggregation, creating a mechanism for tau propagation.
• Understanding these pathways offers potential therapeutic targets for tauopathies.