Department of Pharmaceutical Sciences, University of South Florida Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, Florida 33613, USA.
J Biol Chem. 2012 Jul 13;287(29):24814-20. doi: 10.1074/jbc.M112.367268. Epub 2012 Jun 6.
The RNA-binding protein, trans-active response DNA-binding protein 43 (TDP-43), is normally found in the nucleus, but in amyotrophic lateral sclerosis, frontal temporal dementia, and some cases of Alzheimer disease it is cleaved and mislocalized to the cytosol, leading to accumulation. The mechanisms contributing to this are largely unknown. Here, we show that part of the normal clearance cascade for TDP-43 involves the Cdc37/Hsp90 complex. An Hsp90 inhibitor that disrupts the Cdc37/Hsp90 complex reduced TDP-43 levels to a greater extent than a standard Hsp90 ATPase inhibitor. When Cdc37 was depleted, TDP-43 underwent proteolytic clearance that was dependent on nuclear retrotranslocation and autophagic uptake. Accumulation of the microtubule-associated protein tau prevented the clearance of cleaved TDP-43, but not its production. This caused cleaved TDP-43 to accumulate, a feature observed in the brain of persons with Alzheimer disease. Clearance of cleaved TDP-43 was also prevented by knockdown of the autophagic inducer beclin1. Thus, in cells where TDP-43 clearance is normally needed, a system that employs manipulation of the Hsp90 complex and autophagy exists. But when tau accumulation is occurring, cleaved TDP-43 can no longer be cleared, perhaps explaining the emergence of these co-pathologies.
RNA 结合蛋白，反式激活反应 DNA 结合蛋白 43（TDP-43）通常存在于细胞核中，但在肌萎缩侧索硬化症、额颞叶痴呆和某些阿尔茨海默病病例中，它被切割并错误定位到细胞质中，导致积累。导致这种情况的机制在很大程度上尚不清楚。在这里，我们表明 TDP-43 的正常清除级联的一部分涉及 Cdc37/Hsp90 复合物。破坏 Cdc37/Hsp90 复合物的 Hsp90 抑制剂使 TDP-43 水平降低的程度大于标准 Hsp90 ATP 酶抑制剂。当 Cdc37 耗尽时，TDP-43 经历依赖核逆行和自噬摄取的蛋白水解清除。微管相关蛋白 tau 的积累阻止了裂解 TDP-43 的清除，但不阻止其产生。这导致裂解 TDP-43 积累，这是在患有阿尔茨海默病的人的大脑中观察到的特征。通过敲低自噬诱导剂 beclin1 也可以防止裂解 TDP-43 的清除。因此，在通常需要 TDP-43 清除的细胞中，存在一种利用 Hsp90 复合物和自噬的系统。但是，当 tau 积累发生时，裂解的 TDP-43 就无法再被清除，这也许可以解释这些共病的出现。
