Inhibition of α-synuclein aggregation by small heat shock proteins
Inhibition of α-synuclein aggregation by small heat shock proteins
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DOI：
10.1002/prot.23152
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发表时间：
2011-10-01
影响因子：
2.9
通讯作者：
Verbeek, Marcel M.
中科院分区：
文献类型：
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作者：
Bruinsma, Ilona B.;Bruggink, Kim A.;Verbeek, Marcel M.
α-突触核蛋白(α-syn)的纤化是α-突触核病症发病机制中的关键事件。突变的α-syn(A53T、A30P或E46K)，每个都与家族性帕金森病有关，改变了聚集特性、纤维形态和纤维形成动力学。除了α-syn，路易小体还含有几种相关蛋白，包括小分子热休克蛋白(SHsps)。由于α-syn在细胞内蓄积，sHsps等分子伴侣可能调节α-syn的折叠和聚集。因此，我们研究了sHspsαB-晶体蛋白、Hsp27、Hsp20、HspB8和HspB2B3是否与α-syn结合并影响α-syn的聚集。我们证明了所有的sHSP都与不同的α-SYN结合，尽管结合动力学表明只有弱的和瞬时的相互作用。尽管存在这种短暂的相互作用，但硫代黄素T分析和原子力显微镜显示，各种sHSPs抑制了成熟的α-突触原纤维的形成。有趣的是，HspB8是抑制野生型和突变型α-syn成熟纤维形成的最有效的SHSP。总之，sHSPs可能调节α(-)syn的聚集，因此，sHsps和α-syn之间相互作用的优化可能是α-突触核病发病机制治疗干预的一个有趣的靶点。
The fibrillization of alpha-synuclein (alpha-syn) is a key event in the pathogenesis of alpha-synucleinopathies. Mutant alpha-syn (A53T, A30P, or E46K), each linked to familial Parkinson's disease, has altered aggregation properties, fibril morphologies, and fibrillization kinetics. Besides alpha-syn, Lewy bodies also contain several associated proteins including small heat shock proteins (sHsps). Since alpha-syn accumulates intracellularly, molecular chaperones like sHsps may regulate alpha-syn folding and aggregation. Therefore, we investigated if the sHsps alpha B-crystallin, Hsp27, Hsp20, HspB8, and HspB2B3 bind to alpha-syn and affect alpha-syn aggregation. We demonstrate that all sHsps bind to the various alpha-syns, although the binding kinetics suggests a weak and transient interaction only. Despite this transient interaction, the various sHsps inhibited mature alpha-syn fibril formation as shown by a Thioflavin T assay and atomic force microscopy. Interestingly, HspB8 was the most potent sHsp in inhibiting mature fibril formation of both wild-type and mutant alpha-syn. In conclusion, sHsps may regulate alpha(-)syn aggregation and, therefore, optimization of the interaction between sHsps and alpha-syn may be an interesting target for therapeutic intervention in the pathogenesis of alpha-synucleinopathies.