Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing

作者：Yipeng Wang, Marta Martínez‐Vicente, Ulrike Krüger, Susmita Kaushik, Esther S.P. Wong, Eva‐Maria Mandelkow, Ana María Cuervo, Ana María Cuervo, Eckhard Mandelkow�, Eckhard Mandelkow� · 发表于：Human Molecular Genetics · 年份：2009 · DOI：10.1093/hmg/ddp367 · 被引用次数：616 · 研究领域：Alzheimer's disease research and treatments、Autophagy in Disease and Therapy、Parkinson's Disease Mechanisms and Treatments

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 oli...