In vivo evidence of CHIP up-regulation attenuating tau aggregation
In vivo evidence of CHIP up-regulation attenuating tau aggregation
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DOI：
10.1111/j.1471-4159.2005.03272.x
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发表时间：
2005-09-01
影响因子：
4.7
通讯作者：
Takashima, A
中科院分区：
文献类型：
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作者：
Sahara, N;Murayama, M;Takashima, A
热休克同源 (Hsc)70 相互作用蛋白 (CHIP) 的羧基末端是一种泛素 E3 连接酶，可以与分子伴侣协作，促进蛋白质折叠并防止蛋白质聚集。先前的研究表明，CHIP 与热休克蛋白 (Hsp)70 一起可以调节细胞培养系统中 tau 的泛素化和降解。泛素化 tau 蛋白是神经原纤维缠结 (NFT) 的组成部分，而神经原纤维缠结是阿尔茨海默病 (AD) 的主要组织病理学特征。然而，导致 NFT 形成的确切事件顺序以及所涉及的机制仍不清楚。为了证实 CHIP 在抑制体内 NFT 形成中的作用，我们对人和小鼠大脑中的 CHIP 进行了定量分析。我们发现，与正常对照相比，AD 患者的 CHIP 和 Hsp70 水平有所增加。 AD 和对照中的 CHIP 水平直接对应于 Hsp90 水平，但不对应于 Hsp70 或 Hsc70 水平。在 AD 样品中，CHIP 与肌氨酰不溶性 tau 积累成反比。在 JNPL3 小鼠脑 tau 病模型中，CHIP 广泛分布，但在脊髓中表达较弱，脊髓是 tau 包涵体和神经元丢失最显着的区域。 JNPL3 小鼠小脑区域的 CHIP 蛋白水平显着高于非转基因同窝小鼠。人类 tau 蛋白在小鼠大脑的该区域表达更高，但仅检测到中等水平的肌氨酰不溶性 tau 蛋白。当缺乏 CHIP 的小鼠中不溶性 tau 蛋白积累增加时，这一点得到了证实。这些发现表明，CHIP 的增加可以防止 AD 早期阶段 NFT 的形成。如果得到证实，这将表明神经元中的质量控制机制可能在延缓 tau蛋白病的发病机制中发挥重要作用。
The carboxyl terminus of heat-shock cognate (Hsc)70-interacting protein (CHIP) is a ubiquitin E3 ligase that can collaborate with molecular chaperones to facilitate protein folding and prevent protein aggregation. Previous studies showed that, together with heat-shock protein (Hsp)70, CHIP can regulate tau ubiquitination and degradation in a cell culture system. Ubiquitinated tau is one component in neurofibrillary tangles (NFTs), which are a major histopathological feature of Alzheimer's disease (AD). However, the precise sequence of events leading to NFT formation and the mechanisms involved remain unclear. To confirm CHIP's role in suppressing NFT formation in vivo, we performed a quantitative analysis of CHIP in human and mouse brains. We found increased levels of CHIP and Hsp70 in AD compared with normal controls. CHIP levels in both AD and controls corresponded directly to Hsp90 levels, but not to Hsp70 or Hsc70 levels. In AD samples, CHIP was inversely proportional to sarkosyl-insoluble tau accumulation. In a JNPL3 mouse brain tauopathy model, CHIP was widely distributed but weakly expressed in spinal cord, which was the most prominent region for tau inclusions and neuronal loss. Protein levels of CHIP in cerebellar regions of JNPL3 mice were significantly higher than in non-transgenic littermates. Human tau was more highly expressed in this region of mouse brains, but only moderate levels of sarkosyl-insoluble tau were detected. This was confirmed when increased insoluble tau accumulation was found in mice lacking CHIP. These findings suggest that increases in CHIP may protect against NFT formation in the early stages of AD. If confirmed, this would indicate that the quality-control machinery in a neuron might play an important role in retarding the pathogenesis of tauopathies.