Klucken Jochen, Shin Youngah, Masliah Eliezer, Hyman Bradley T, McLean Pamela J
Alzheimer's Disease Research Laboratory, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
J Biol Chem. 2004 Jun 11;279(24):25497-502. doi: 10.1074/jbc.M400255200. Epub 2004 Mar 25.
Aggregation and cytotoxicity of misfolded alpha-synuclein is postulated to be crucial in the disease process of neurodegenerative disorders such as Parkinson's disease and DLB (dementia with Lewy bodies). In this study, we detected misfolded and aggregated alpha-synuclein in a Triton X-100 insoluble fraction as well as a high molecular weight product by gel electrophoresis of temporal neocortex from DLB patients but not from controls. We also found similar Triton X-100 insoluble forms of alpha-synuclein in an alpha-synuclein transgenic mouse model and in an in vitro model of alpha-synuclein aggregation. Introducing the molecular chaperone Hsp70 into the in vivo model by breeding alpha-synuclein transgenic mice with Hsp70-overexpressing mice led to a significant reduction in both the high molecular weight and detergent-insoluble alpha-synuclein species. Concomitantly, we found that Hsp70 overexpression in vitro similarly reduced detergent-insoluble alpha-synuclein species and protected cells from alpha-synuclein-induced cellular toxicity. Taken together, these data demonstrate that the molecular chaperone Hsp70 can reduce the amount of misfolded, aggregated alpha-synuclein species in vivo and in vitro and protect it from alpha-synuclein-dependent toxicity.
错误折叠的α-突触核蛋白的聚集和细胞毒性被认为在帕金森病和路易体痴呆（DLB）等神经退行性疾病的发病过程中至关重要。在本研究中，我们在DLB患者而非对照者的颞叶新皮质的Triton X-100不溶性部分以及通过凝胶电泳检测到的高分子量产物中检测到错误折叠和聚集的α-突触核蛋白。我们还在α-突触核蛋白转基因小鼠模型和α-突触核蛋白聚集的体外模型中发现了类似的Triton X-100不溶性形式的α-突触核蛋白。通过将α-突触核蛋白转基因小鼠与过表达Hsp70的小鼠杂交，将分子伴侣Hsp70引入体内模型，导致高分子量和去污剂不溶性α-突触核蛋白种类均显著减少。同时，我们发现体外过表达Hsp70同样减少了去污剂不溶性α-突触核蛋白种类，并保护细胞免受α-突触核蛋白诱导的细胞毒性。综上所述，这些数据表明分子伴侣Hsp70可以在体内和体外减少错误折叠、聚集的α-突触核蛋白种类的数量，并保护其免受α-突触核蛋白依赖性毒性。
