Wright Josephine A, Wang Xiaoyan, Brown David R
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
FASEB J. 2009 Aug;23(8):2384-93. doi: 10.1096/fj.09-130039. Epub 2009 Mar 26.
Parkinson's disease and a number of other neurodegenerative diseases have been linked to either genetic mutations in the alpha-synuclein gene or show evidence of aggregates of the alpha-synuclein protein, sometimes in the form of Lewy bodies. There currently is no clear evidence of a distinct neurotoxic species of alpha-synuclein to explain the death of neurons in these diseases. We undertook to assess the toxicity of alpha-synuclein via exogenous application in cell culture. Initially, we showed that only aggregated alpha-synuclein is neurotoxic and requires the presence copper but not iron. Other members of the synuclein family showed no toxicity in any form and inherited point mutations did not alter the effective toxic concentration of alpha-synuclein. Through protein fractionation techniques, we were able to isolate an oligomeric species responsible for the toxicity of alpha-synuclein. This oligomeric species has a unique stellate appearance under EM and again, requires association with copper to induce cell death. The results allow us to suggest that the toxic species of alpha-synuclein in vivo could possibly be these stellate oligomers and not fibrils. Our data provide a link between the recently noted association of copper and alpha-synuclein and a potential role for the combination in causing neurodegeneration.
帕金森病和许多其他神经退行性疾病与α-突触核蛋白基因的基因突变有关,或者表现出α-突触核蛋白聚集的证据,有时以路易小体的形式出现。目前尚无明确证据表明存在一种独特的具有神经毒性的α-突触核蛋白物种来解释这些疾病中神经元的死亡。我们通过在细胞培养中外源应用来评估α-突触核蛋白的毒性。最初,我们发现只有聚集的α-突触核蛋白具有神经毒性,且需要铜的存在而非铁。突触核蛋白家族的其他成员未表现出任何形式的毒性,遗传性点突变也未改变α-突触核蛋白的有效毒性浓度。通过蛋白质分级分离技术,我们能够分离出一种导致α-突触核蛋白毒性的寡聚体物种。这种寡聚体物种在电子显微镜下具有独特的星状外观,同样需要与铜结合才能诱导细胞死亡。这些结果使我们认为,体内α-突触核蛋白的毒性物种可能是这些星状寡聚体而非纤维。我们的数据为最近发现的铜与α-突触核蛋白之间的关联以及二者结合在导致神经退行性变中的潜在作用提供了联系。