CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation
CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation
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DOI：
10.1093/hmg/ddh083
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发表时间：
2004-04-01
影响因子：
3.5
通讯作者：
Hutton, M
中科院分区：
文献类型：
--
作者：
Petrucelli, L;Dickson, D;Hutton, M
分子伴侣、泛素连接酶和蛋白酶体损伤与一些神经退行性疾病有关，包括阿尔茨海默病和帕金森病，这些疾病的特征是异常蛋白质聚集(例如，分别是tau和α-突触核蛋白)。在这里，我们报道了CHIP，一种直接与Hsp70/90相互作用的泛素连接酶，诱导微管相关蛋白tau的泛素化。芯片还会增加tau的聚集。与这一观察结果相一致的是，在人死后组织中的各种tau病变被发现为芯片免疫阳性。相反，通过格尔达霉素或热休克因子1诱导HSP70导致tau稳态水平下降，并选择性地减少洗涤剂不溶性tau。此外，30个月大的小鼠过表达可诱导的HSP70后，tau水平显著降低。综上所述，这些数据表明Hsp70/ChIP伴侣系统在调节tau周转和选择性消除异常tau物种方面发挥重要作用。因此，HSP70/CHIP可能在肌萎缩侧索硬化症的发病机制中发挥重要作用，也是一个潜在的治疗靶点。
Molecular chaperones, ubiquitin ligases and proteasome impairment have been implicated in several neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by accumulation of abnormal protein aggregates (e.g. tau and alpha-synuclein respectively). Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau. CHIP also increases tau aggregation. Consistent with this observation, diverse of tau lesions in human postmortem tissue were found to be immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor 1 leads to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 show a significant reduction in tau levels. Together these data demonstrate that the Hsp70/CHIP chaperone system plays an important role in the regulation of tau turnover and the selective elimination of abnormal tau species. Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target.