Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing
Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing
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DOI：
10.1093/hmg/ddp367
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发表时间：
2009-11-01
影响因子：
3.5
通讯作者：
Mandelkow, Eckhard
中科院分区：
文献类型：
--
作者：
Wang, Yipeng;Martinez-Vicente, Marta;Mandelkow, Eckhard
聚集和切割是阿尔茨海默病(AD)Tau病理的两个特征，Tau的异常碎裂被认为是Tau成对螺旋细丝成核的原因。通过泛素-蛋白酶体和自噬-溶酶体途径清除异常修饰的蛋白质，这是细胞中蛋白质降解的两条主要途径。关于这些途径中的哪一条有助于清除AD中的Tau蛋白和形成的异常Tau聚集体，目前还存在争议。在这里，我们在一个可诱导的神经细胞模型中证明，自噬-溶酶体系统有助于将Tau碎裂成有利于聚集的形式，并有助于清除Tau聚集。抑制巨噬细胞可增强Tau的聚集和细胞毒性。Tau重复结构域可以被胞浆蛋白水解酶在N端附近切割，从而产生片段F1。溶酶体组织蛋白L还需要在C末端附近进行额外的切割，以产生高度淀粉样变性的Tau片段F2和F3，并能够播种Tau的聚集。我们在这项工作中发现，一种选择性形式的自噬，即伴侣介导的自噬，参与了胞浆Tau向溶酶体的递送，以实现这种有限的切割。然而，F1没有完全进入溶酶体，但仍然与溶酶体膜相关。Tau片段在溶酶体膜上的低效移位似乎促进了这些细胞器表面Tau寡聚体的形成，这可能是聚集的前体，并干扰了溶酶体的功能。
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.