CHIP targets toxic α-synuclein oligomers for degradation
CHIP targets toxic α-synuclein oligomers for degradation
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DOI：
10.1074/jbc.m802283200
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发表时间：
2008-06-27
影响因子：
4.8
通讯作者：
McLean, Pamela J.
中科院分区：
文献类型：
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作者：
Tetzlaff, Julie E.;Putcha, Preeti;McLean, Pamela J.
α-突触核蛋白（α-Syn）可以自缔合，形成寡聚体、原纤维和路易体，这是帕金森病的病理标志。目前的教条表明，寡聚体α-Syn中间体可能代表最具毒性的α-Syn物质。在这里，我们研究了一种有效的分子伴侣，CHIP（热休克蛋白70相互作用蛋白的羧基末端），α Syn寡聚化的影响，使用一种新的双分子荧光互补分析。CHIP是一种多结构域伴侣蛋白，利用三肽/热休克蛋白70结合结构域和U盒/泛素连接酶结构域来差异地影响错误折叠蛋白的命运。在目前的研究中，我们发现CHIP的共表达通过特异性降解毒性α-Syn寡聚体，以一种依赖于三肽结构域、不依赖于U盒的方式选择性地降低α-Syn寡聚化和毒性。我们的结论是，CHIP优先识别和介导的毒性，寡聚体形式的α-Syn的降解。进一步阐明CHIP诱导的寡聚体α-Syn降解的机制可能有助于通过模拟或增强CHIP的强大作用来成功开发靶向寡聚体α-Syn的药物疗法。
alpha-Synuclein (alpha Syn) can self-associate, forming oligomers, fibrils, and Lewy bodies, the pathological hallmark of Parkinson disease. Current dogma suggests that oligomeric alpha Syn intermediates may represent the most toxic alpha Syn species. Here, we studied the effect of a potent molecular chaperone, CHIP ( carboxyl terminus of Hsp70- interacting protein), on alpha Syn oligomerization using a novel bimolecular fluorescence complementation assay. CHIP is a multidomain chaperone, utilizing both a tetratricopeptide/Hsp70 binding domain and a U-box/ubiquitin ligase domain to differentially impact the fate of misfolded proteins. In the current study, we found that co-expression of CHIP selectively reduced alpha Syn oligomerization and toxicity in a tetratricopeptide domain-dependent, U-box-independent manner by specifically degrading toxic alpha Syn oligomers. We conclude that CHIP preferentially recognizes and mediates degradation of toxic, oligomeric forms of alpha Syn. Further elucidation of the mechanisms of CHIP-induced degradation of oligomeric alpha Syn may contribute to the successful development of drug therapies that target oligomeric alpha Syn by mimicking or enhancing the powerful effects of CHIP.