Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies
Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies
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DOI：
10.1073/pnas.0701055104
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发表时间：
2007-05-29
影响因子：
11.1
通讯作者：
Chiosis, Gabriela
中科院分区：
文献类型：
--
作者：
Luo, Wenjie;Dou, Fei;Chiosis, Gabriela
神经变性是多种失调事件的结果，是一个漫长的多步骤过程，表现为突变变体的增加和异常表达、翻译后修饰和某些蛋白质的加工。这些失调过程的积累需要一种机制来维持其功能稳定性并允许神经退行性表型的进化。在恶性细胞中，缓冲转化的能力归因于热休克蛋白 90 (Hsp90)。尽管正常蛋白质似乎需要伴侣分子的有限帮助，但其异常蛋白质似乎高度依赖于 Hsp90。虽然在几种癌蛋白中观察到 Hsp90 对突变或功能失调的客户蛋白的亲和力增强，但尚不清楚 Hsp90 是否对神经元蛋白发挥类似的作用，从而维持和促进神经退行性疾病中的转化表型。 Tau 病是一种神经退行性疾病，其特征是 Tau 蛋白的异常磷酸化和/或表达，导致 Tau 聚集物的时间依赖性积累和随后的神经元死亡。在这里，我们发现p35（一种神经元蛋白，通过形成复合物导致异常的Tau磷酸化激活细胞周期蛋白依赖性蛋白激酶5）以及突变体而非WT Tau蛋白的稳定性在tau蛋白病中由Hsp90维持。在 tau 蛋白病的细胞和小鼠模型中抑制 Hsp90 会导致这些蛋白的致病活性降低，并导致聚集的 Tau 消除。结果确定了 Hsp90 在维持和促进这些疾病的退行性表型中发挥的重要作用，并提供了控制癌症和神经退行性疾病的共同原则。
Neurodegeneration, a result of multiple dysregulatory events, is a lengthy multistep process manifested by accrual of mutant variants and abnormal expression, posttranslational modification, and processing of certain proteins. Accumulation of these dysregulated processes requires a mechanism that maintains their functional stability and allows the evolution of the neurodegenerative phenotype. In malignant cells, the capacity to buffer transformation has been attributed to heat-shock protein 90 (Hsp90). Although normal proteins seem to require limited assistance from the chaperone, their aberrant counterparts seem to be highly dependent on Hsp90. Whereas enhanced Hsp90 affinity for mutated or functionally deregulated client proteins has been observed for several oncoproteins, it is unknown whether Hsp90 plays a similar role for neuronal proteins and thus maintains and facilitates the transformed phenotype in neurodegenerative diseases. Tauopathies are neurodegenerative diseases characterized by aberrant phosphorylation and/or expression of Tau protein, leading to a time-dependent accumulation of Tau aggregates and subsequent neuronal death. Here, we show that the stability of p35, a neuronal protein that activates cyclin-dependent protein kinase 5 through complex formation leading to aberrant Tau phosphorylation, and that of mutant but not WT Tau protein is maintained in tauopathies by Hsp90. Inhibition of Hsp90 in cellular and mouse models of tauopathies leads to a reduction of the pathogenic activity of these proteins and results in elimination of aggregated Tau. The results identify important roles played by Hsp90 in maintaining and facilitating the degenerative phenotype in these diseases and provide a common principle governing cancer and neurodegenerative diseases.