Zhou H, Li S H, Li X J
Department of Genetics, Emory University, School of Medicine, Atlanta, Georgia 30322, USA.
J Biol Chem. 2001 Dec 21;276(51):48417-24. doi: 10.1074/jbc.M104140200. Epub 2001 Oct 17.
Polyglutamine protein aggregation is associated with eight inherited neurodegenerative disorders. In Huntington's disease, N-terminal fragments of mutant huntingtin form intracellular aggregates and mediate cellular toxicity. Recent studies have shown that chaperones inhibit polyglutamine-mediated aggregation and cellular toxicity. Because chaperones also inhibit caspase activation to protect cells from death, it remains unclear whether the protective effect of chaperones on polyglutamine-mediated cellular toxicity is dependent on their inhibition of protein aggregation. In this study, we show that several chaperones including HSP 40, HSP 70, and N-ethylmaleimide-sensitive factor can inhibit cellular toxicity caused by N-terminal mutant huntingtin fragments. However, only HSP 40 is able to inhibit huntingtin aggregation. Furthermore, time-course study suggests that the protection of chaperones against huntingtin toxicity is not the result of their suppression of huntingtin aggregation. Chaperones inhibit caspase-3 and caspase-9 activation mediated by mutant huntingtin, and this inhibition is independent of huntingtin aggregation. We propose that the inhibition of caspase activity by chaperones is involved in their suppression of polyglutamine toxicity.
聚谷氨酰胺蛋白聚集与八种遗传性神经退行性疾病相关。在亨廷顿舞蹈症中，突变型亨廷顿蛋白的N端片段形成细胞内聚集体并介导细胞毒性。最近的研究表明，分子伴侣可抑制聚谷氨酰胺介导的聚集和细胞毒性。由于分子伴侣还能抑制半胱天冬酶激活以保护细胞免于死亡，因此尚不清楚分子伴侣对聚谷氨酰胺介导的细胞毒性的保护作用是否依赖于其对蛋白质聚集的抑制。在本研究中，我们表明包括热休克蛋白40（HSP 40）、热休克蛋白70（HSP 70）和N - 乙基马来酰亚胺敏感因子在内的几种分子伴侣可抑制N端突变型亨廷顿蛋白片段引起的细胞毒性。然而，只有HSP 40能够抑制亨廷顿蛋白聚集。此外，时间进程研究表明，分子伴侣对亨廷顿蛋白毒性的保护作用并非其抑制亨廷顿蛋白聚集的结果。分子伴侣抑制突变型亨廷顿蛋白介导的半胱天冬酶 - 3和半胱天冬酶 - 9激活，且这种抑制与亨廷顿蛋白聚集无关。我们提出，分子伴侣对半胱天冬酶活性的抑制参与了其对聚谷氨酰胺毒性的抑制。
