Pre-fibrillar α-synuclein variants with impaired β-structure increase neurotoxicity in Parkinson's disease models
Pre-fibrillar α-synuclein variants with impaired β-structure increase neurotoxicity in Parkinson's disease models
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DOI：
10.1038/emboj.2009.257
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发表时间：
2009-10-21
期刊：
影响因子：
11.4
通讯作者：
Zweckstetter, Markus
中科院分区：
文献类型：
--
作者：
Karpinar, Damla Pinar;Balija, Madhu Babu Gajula;Zweckstetter, Markus
α-突触核蛋白（alpha-synuclein，alpha S）聚集与帕金森病（Parkinson's disease，PD）的关系早已被人们所认识，但其毒性机制、致病种类及其分子特性尚未被确定。为了深入了解不同聚集的α S物种在体内神经毒性中的功能，我们通过基于结构的合理设计产生了α S变体。生物物理分析显示，α S突变体具有降低的纤维化倾向，但形成增加量的可溶性寡聚体。为了评估它们在体内的生物学反应，我们研究了在组织培养细胞、哺乳动物神经元和PD模型生物（如秀丽隐杆线虫和黑腹果蝇）中表达后生物药理学定义的前纤维状α S突变体的作用。结果显示，α S聚集体与受损的β结构、神经元毒性和行为缺陷之间存在显著相关性，并且它们在多聚体aS物质的生物物理性质与其体内功能之间建立了紧密联系。The EMBO Journal（2009）28，3256-3268. doi：10.1038/doj.2009.257; 2009年9月10日在线发布
The relation of alpha-synuclein (alpha S) aggregation to Parkinson's disease (PD) has long been recognized, but the mechanism of toxicity, the pathogenic species and its molecular properties are yet to be identified. To obtain insight into the function different aggregated alpha S species have in neurotoxicity in vivo, we generated alpha S variants by a structure-based rational design. Biophysical analysis revealed that the alpha S mutants have a reduced fibrillization propensity, but form increased amounts of soluble oligomers. To assess their biological response in vivo, we studied the effects of the biophysically defined pre-fibrillar alpha S mutants after expression in tissue culture cells, in mammalian neurons and in PD model organisms, such as Caenorhabditis elegans and Drosophila melanogaster. The results show a striking correlation between alpha S aggregates with impaired beta-structure, neuronal toxicity and behavioural defects, and they establish a tight link between the biophysical properties of multimeric aS species and their in vivo function. The EMBO Journal (2009) 28, 3256-3268. doi:10.1038/emboj.2009.257; Published online 10 September 2009