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患有FTLD的ALS病理性TDP-43丝的结构

Diana Arseni¹, Masato Hasegawa², Alexey G Murzin¹

¹MRC Laboratory of Molecular Biology, Cambridge, UK.

|December 9, 2021

概括

研究人员确定了像ALS和FTLD这样的神经退行性疾病中的聚合TARDNA结合蛋白43kDa (TDP-43) 的结构. 这一发现揭示了一种新的双螺旋,与体外结构不同,提供了新的治疗点.

科学领域:

神经科学
结构生物学
生物化学

背景情况:

43 kDa的TARDNA结合蛋白 (TDP-43) 的异常聚合是肌缩侧面硬化 (ALS) 和前叶退化 (FTLD) 的关键病理特征.
目前对神经退行性疾病中的TDP-43聚合结构的了解有限,阻碍了向治疗的开发.
目前没有疾病修饰治疗或早期诊断方法可用于这些疾病.

研究的目的:

确定ALS和FTLD患者大脑中发现的病态TDP-43聚合物的高分辨率结构.
阐明TDP-43纤维的分子结构,并将其与体外形成的结构进行比较.

主要方法:

使用冷电子显微镜 (cryo-EM) 来分析两名被诊断患有ALS和FTLD的前额和运动皮层的聚合TDP-43.
结构分析的重点是确定TDP-43在粉样纤维中的折叠和排列.

主要成果:

在研究的两个大脑区域和个体中都发现了相同的粉样丝结构.
顺序的光纤核心,跨越TDP-43的低复杂性域的282-360,采用了新的双螺旋折叠.
这种独特的折叠缺乏交叉β氨基酸结构,因为β链的长度有限,并且没有β片堆叠,其明显的表面表明潜在的连接位.

结论:

病态TDP-43丝的确定的结构为ALS和FTLD的分子病变提供了关键的见解.
这些结构信息可以指导针对TDP-43蛋白病变的诊断和治疗策略的制定.

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