Department of Molecular Medicine, University of South Florida Health Byrd Alzheimer's Institute, Tampa, Florida 33613, USA.
J Neurosci. 2010 Nov 17;30(46):15374-82. doi: 10.1523/JNEUROSCI.3155-10.2010.
Molecular chaperones regulate the aggregation of a number of proteins that pathologically misfold and accumulate in neurodegenerative diseases. Identifying ways to manipulate these proteins in disease models is an area of intense investigation; however, the translation of these results to the mammalian brain has progressed more slowly. In this study, we investigated the ability of one of these chaperones, heat shock protein 27 (Hsp27), to modulate tau dynamics. Recombinant wild-type Hsp27 and a genetically altered version of Hsp27 that is perpetually pseudo-phosphorylated (3×S/D) were generated. Both Hsp27 variants interacted with tau, and atomic force microscopy and dynamic light scattering showed that both variants also prevented tau filament formation. However, extrinsic genetic delivery of these two Hsp27 variants to tau transgenic mice using adeno-associated viral particles showed that wild-type Hsp27 reduced neuronal tau levels, whereas 3×S/D Hsp27 was associated with increased tau levels. Moreover, rapid decay in hippocampal long-term potentiation (LTP) intrinsic to this tau transgenic model was rescued by wild-type Hsp27 overexpression but not by 3×S/D Hsp27. Because the 3×S/D Hsp27 mutant cannot cycle between phosphorylated and dephosphorylated states, we can conclude that Hsp27 must be functionally dynamic to facilitate tau clearance from the brain and rescue LTP; however, when this property is compromised, Hsp27 may actually facilitate accumulation of soluble tau intermediates.
分子伴侣调节许多蛋白质的聚集,这些蛋白质在神经退行性疾病中病理性错误折叠并积累。鉴定在疾病模型中操纵这些蛋白质的方法是一个研究热点;然而,这些结果在哺乳动物大脑中的转化进展得更为缓慢。在这项研究中,我们研究了一种伴侣蛋白,热休克蛋白 27(Hsp27),调节 tau 动态的能力。生成了重组野生型 Hsp27 和一种遗传改变的 Hsp27,该 Hsp27 持续假磷酸化(3×S/D)。两种 Hsp27 变体都与 tau 相互作用,原子力显微镜和动态光散射显示这两种变体都能阻止 tau 丝形成。然而,通过腺相关病毒颗粒将这两种 Hsp27 变体的外源性遗传递送至 tau 转基因小鼠,野生型 Hsp27 降低了神经元 tau 水平,而 3×S/D Hsp27 与 tau 水平升高相关。此外,这种 tau 转基因模型中固有海马长时程增强(LTP)的快速衰减被野生型 Hsp27 的过表达挽救,但 3×S/D Hsp27 则不能。由于 3×S/D Hsp27 突变体不能在磷酸化和去磷酸化状态之间循环,我们可以得出结论,Hsp27 必须具有功能动态性才能促进大脑中 tau 的清除并挽救 LTP;然而,当这种特性受到损害时,Hsp27 实际上可能促进可溶性 tau 中间产物的积累。