Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing
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Open Access
- 4 August 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 18 (21) , 4153-4170
- https://doi.org/10.1093/hmg/ddp367
Abstract
Aggregation and cleavage are two hallmarks of Tau pathology in Alzheimer disease (AD), and abnormal fragmentation of Tau is thought to contribute to the nucleation of Tau paired helical filaments. Clearance of the abnormally modified protein could occur by the ubiquitin–proteasome and autophagy–lysosomal pathways, the two major routes for protein degradation in cells. There is a debate on which of these pathways contributes to clearance of Tau protein and of the abnormal Tau aggregates formed in AD. Here, we demonstrate in an inducible neuronal cell model of tauopathy that the autophagy–lysosomal system contributes to both Tau fragmentation into pro-aggregating forms and to clearance of Tau aggregates. Inhibition of macroautophagy enhances Tau aggregation and cytotoxicity. The Tau repeat domain can be cleaved near the N terminus by a cytosolic protease to generate the fragment F1. Additional cleavage near the C terminus by the lysosomal protease cathepsin L is required to generate Tau fragments F2 and F3 that are highly amyloidogenic and capable of seeding the aggregation of Tau. We identify in this work that components of a selective form of autophagy, chaperone-mediated autophagy, are involved in the delivery of cytosolic Tau to lysosomes for this limited cleavage. However, F1 does not fully enter the lysosome but remains associated with the lysosomal membrane. Inefficient translocation of the Tau fragments across the lysosomal membrane seems to promote formation of Tau oligomers at the surface of these organelles which may act as precursors of aggregation and interfere with lysosomal functioning.Keywords
This publication has 79 references indexed in Scilit:
- Autophagy fights disease through cellular self-digestionNature, 2008
- Dopamine-modified α-synuclein blocks chaperone-mediated autophagyJournal of Clinical Investigation, 2008
- Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell modelProceedings of the National Academy of Sciences, 2007
- Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathiesProceedings of the National Academy of Sciences, 2007
- Calpain-Cleavage of α-SynucleinThe American Journal of Pathology, 2007
- The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteinsJournal of Clinical Investigation, 2007
- Suppression of basal autophagy in neural cells causes neurodegenerative disease in miceNature, 2006
- Consequences of the selective blockage of chaperone-mediated autophagyProceedings of the National Academy of Sciences, 2006
- Proteases Acting on Mutant Huntingtin Generate Cleaved Products that Differentially Build Up Cytoplasmic and Nuclear InclusionsPublished by Elsevier ,2002
- The τ Protein in Human Cerebrospinal Fluid in Alzheimer's Disease Consists of Proteolytically Derived FragmentsJournal of Neurochemistry, 1997