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播种TDP-43的聚合需要纤维化后的蛋白质分解裂变

Senthil T Kumar¹, Sergey Nazarov¹, Sílvia Porta²

¹Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, EPFL, Lausanne, Switzerland.

Nature neuroscience

|May 29, 2023

概括

研究人员创造了人造的交换性反应DNA结合蛋白43 (TDP-43) 丝. 揭露粉样核的裂是TDP-43病理在神经退行性疾病 (如ALS) 中传播的关键.

科学领域:

神经科学是一个神经科学.
分子生物学分子生物学
生物化学生物化学

背景情况:

交换性反应DNA结合蛋白43 (TDP-43) 聚合是前叶退化和肌缩性侧面硬化症的核心.
导致TDP-43神经毒性的精确序列和结构因素尚未完全理解.

研究的目的:

开发一种生产重组TDP-43纤维的方法.
研究TDP-43.3的结构特征和聚合机制.
为了确定TDP-43蛋白病变的潜在治疗点.

主要方法:

生产全长重组TDP-43丝材.
使用生物物理技术对TDP-43纤维的结构分析.
细胞测试以评估TDP-43病理的播种和传播.

主要成果:

重组的TDP-43纤维丝在序列和形态上模仿来自大脑的纤维丝.
TDP-43 细丝具有一个埋藏的,富含β-叶片的粉样核.
暴露粉样核的蛋白质分解裂变对于TDP-43病理的传播和播种至关重要.
暴露的粉样核纤维有效地在细胞中播种内源性TDP-43聚合.

结论:

TDP-43的光纤结构和裂变对于疾病的发病是至关重要的.
抑制分裂TDP-43聚合物的酶可能为ALS和其他TDP-43蛋白质病变提供治疗策略.

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