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J Biol Chem. 2018 Feb 16;293(7):2438-2451. doi: 10.1074/jbc.M117.809293. Epub 2017 Dec 27.

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

Author information

1
From the MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom.
2
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom, and.
3
From the MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom, mg@mrc-lmb.cam.ac.uk.
4
Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.

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.

KEYWORDS:

NDP52; Tau protein (Tau); autophagy; galectin; galectin-8; neurodegeneration; p62 (sequestosome 1 (SQSTM1)); prion-like; protein aggregation; seeded aggregation; tauopathy

PMID:
29282296
PMCID:
PMC5818177
DOI:
10.1074/jbc.M117.809293
[Indexed for MEDLINE]
Free PMC Article

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