Department of Chemistry, University of Cambridge, Cambridge, UK.
EMBO J. 2009 Dec 2;28(23):3758-70. doi: 10.1038/emboj.2009.298. Epub 2009 Oct 29.
The ATP-dependent protein chaperone heat-shock protein 70 (Hsp70) displays broad anti-aggregation functions and has a critical function in preventing protein misfolding pathologies. According to in vitro and in vivo models of Parkinson's disease (PD), loss of Hsp70 activity is associated with neurodegeneration and the formation of amyloid deposits of alpha-synuclein (alphaSyn), which constitute the intraneuronal inclusions in PD patients known as Lewy bodies. Here, we show that Hsp70 depletion can be a direct result of the presence of aggregation-prone polypeptides. We show a nucleotide-dependent interaction between Hsp70 and alphaSyn, which leads to the aggregation of Hsp70, in the presence of ADP along with alphaSyn. Such a co-aggregation phenomenon can be prevented in vitro by the co-chaperone Hip (ST13), and the hypothesis that it might do so also in vivo is supported by studies of a Caenorhabditis elegans model of alphaSyn aggregation. Our findings indicate that a decreased expression of Hip could facilitate depletion of Hsp70 by amyloidogenic polypeptides, impairing chaperone proteostasis and stimulating neurodegeneration.
ATP 依赖的蛋白伴侣热休克蛋白 70（Hsp70）具有广泛的抗聚集功能，并在预防蛋白质错误折叠病理方面起着关键作用。根据帕金森病（PD）的体外和体内模型，Hsp70 活性的丧失与神经退行性变和 alpha-突触核蛋白（alphaSyn）的淀粉样沉积的形成有关，alphaSyn 构成了 PD 患者中称为路易体的神经元内包涵体。在这里，我们表明 Hsp70 的耗竭可能是聚集倾向多肽存在的直接结果。我们显示了在 ADP 存在下，Hsp70 与 alphaSyn 之间存在核苷酸依赖性相互作用，导致 Hsp70 的聚集。这种共聚集现象可以通过共伴侣 Hip（ST13）在体外得到预防，并且通过 alphaSyn 聚集的秀丽隐杆线虫模型的研究支持了它也可能在体内这样做的假设。我们的发现表明，Hip 的表达降低可能会通过淀粉样多肽导致 Hsp70 的耗竭，从而损害伴侣蛋白稳态并刺激神经退行性变。
