Cross-seeding by prion protein inactivates TDP-43
Cross-seeding by prion protein inactivates TDP-43
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DOI：
10.1093/brain/awad289
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发表时间：
2024-01-04
期刊：
影响因子：
14.5
通讯作者：
Tatzelt，Joerg
中科院分区：
文献类型：
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作者：
Polido，Stella A.;Stuani，Cristiana;Tatzelt，Joerg
各种神经退行性疾病的共同病理特征是蛋白质聚集体的积累。神经毒性作用是由聚集蛋白的生理活性丧失和/或错误折叠的蛋白质构象的毒性功能获得引起的。在传染性海绵状脑病或朊病毒疾病中，神经变性是由朊病毒蛋白（PrP）的异常折叠亚型引起的。然而，人们对致病性PrP构象如何干扰神经元活力知之甚少。通过体外方法、细胞培养、动物模型和患者脑样本，我们发现错误折叠的PrP可以诱导TAR dna结合蛋白43 （TDP-43）聚集和失活。纯化的PrP聚集体在体外和细胞内与TDP-43相互作用，并诱导可溶性TDP-43转化为非动态蛋白组合。类似地，胞质中错误定位的PrP构象结合并将TDP-43隔离在胞质聚集体中。因此，细胞核中依赖tdp -43的剪接活性显著降低，导致胞质内PrP聚集的细胞中蛋白表达改变。最后，我们提出了在表达哺乳动物PrP和克雅氏病患者的转基因果蝇的神经元中存在胞质TDP-43聚集的证据。我们的研究通过交叉播种确定了异常PrP构象如何损害生理通路的新机制。
A common pathological denominator of various neurodegenerative diseases is the accumulation of protein aggregates. Neurotoxic effects are caused by a loss of the physiological activity of the aggregating protein and/or a gain of toxic function of the misfolded protein conformers. In transmissible spongiform encephalopathies or prion diseases, neurodegeneration is caused by aberrantly folded isoforms of the prion protein (PrP). However, it is poorly understood how pathogenic PrP conformers interfere with neuronal viability. Employingin vitroapproaches, cell culture, animal models and patients’ brain samples, we show that misfolded PrP can induce aggregation and inactivation of TAR DNA-binding protein-43 (TDP-43).Purified PrP aggregates interact with TDP-43in vitroand in cells and induce the conversion of soluble TDP-43 into non-dynamic protein assemblies. Similarly, mislocalized PrP conformers in the cytosol bind to and sequester TDP-43 in cytosolic aggregates. As a consequence, TDP-43-dependent splicing activity in the nucleus is significantly decreased, leading to altered protein expression in cells with cytosolic PrP aggregates. Finally, we present evidence for cytosolic TDP-43 aggregates in neurons of transgenic flies expressing mammalian PrP and Creutzfeldt–Jakob disease patients.Our study identified a novel mechanism of how aberrant PrP conformers impair physiological pathways by cross-seeding.