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在S129α-synuclein残留物的单点突变及其对结构,聚合和神经毒性的影响

Esha Pandit¹, Lopamudra Das¹, Anoy Kumar Das²

¹Structural Biology and Bioinformatics Division, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, India.

Frontiers in chemistry

|June 12, 2023

概括

与帕金森病相关的α-synuclein (aS) 蛋白的突变减少了其聚合和毒性. 突变S129A和S129W突变显示稳定性增加,对神经元细胞的有害影响较小.

科学领域:

神经科学是一个神经科学.
生物化学生物化学
结构生物学结构生物学

背景情况:

帕金森病的病理学涉及到α-synuclein (aS) 的聚合物,这是一个内在失序的蛋白质.
aS的C端域对其溶解性和稳定性至关重要.
研究aS中的突变可以揭示疾病机制的洞察力.

研究的目的:

为了检查两个单点突变 (S129A和S129W) 在人类α-synuclein (aS) 的C端域中的结构和聚合特性.
为了比较这些突变的聚合动力学和细胞毒性与野生类型aS (wt aS).

主要方法:

循环二元化 (CD) 和拉曼光谱分析二次结构.
提奥夫拉T测定和原子力显微镜用于研究聚合.
使用SH-SY5Y神经元细胞系进行细胞毒性测定.

主要成果:

突变S129A和S129W表现出增强的结构稳定性和更大的倾向于阿尔法螺旋形状相比wt aS.
突变者的α螺旋倾向导致延长滞后阶段,并降低了富含β片纤维化的β片纤维化的增长率.
从wt aS形成的寡合体对神经元细胞有显著更大的毒性 (~40%的存活率) 比来自突变蛋白质的寡合体 (~80%的存活率).

结论:

在S129A和S129W突变赋予结构稳定性和阿尔法螺旋倾向aS.
这种改变的结构导致较慢的寡合化和纤维化率.
突变的聚合减少和结构改变有助于它们对神经元细胞的毒性降低,为帕金森病提供了潜在的治疗见解.

关键词:

拉曼·拉曼,拉曼·拉曼,拉曼·拉曼.这是一种α-synuclein.氨基化物氨基化物纤维化 - 纤维化神经毒性的作用.二级结构是二级结构的二次结构.

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