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TDP-43聚集的播散需要纤维化后的蛋白水解作用
作者:小柯机器人 发布时间:2023/6/1 15:50:46

瑞士洛桑联邦理工学院Hilal A. Lashuel小组发现,TDP-43聚集的播散需要纤维化后的蛋白水解作用。2023年5月29日,《自然—神经科学》杂志在线发表了这项成果。

研究人员提出了一种生产重组全长反式激活应答DNA结合蛋白43(TDP-43)丝的新方法,其序列和形态特征与脑源性TDP-43细丝相似。结果表明,TDP-43丝包含一个富含β-片的螺旋状淀粉质核心,该核心被蛋白质的侧翼结构域完全掩盖。研究人员证明,TDP-43丝的蛋白水解切割和这个淀粉样核心的暴露是传播TDP-43病理和增强脑源性TDP-43聚集物种子所需的。只有具有暴露的淀粉样核心的TDP-43丝能有效地在细胞中播种内源性TDP-43的聚集。这些发现表明,抑制介导TDP-43聚集物切割的酶是一种可行的疾病改变策略,进而减缓肌萎缩性脊髓侧索硬化症和其他TDP-43蛋白病的进展。

据悉,尽管有强有力的证据表明TDP-43的聚集与带TDP-43的额颞叶变性、肌萎缩侧索硬化症和一些神经退行性疾病的发病机制有关,但人们对其聚集和神经毒性的序列和结构决定因素的了解仍然不完整。

附:英文原文

Title: Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage

Author: Kumar, Senthil T., Nazarov, Sergey, Porta, Slvia, Maharjan, Niran, Cendrowska, Urszula, Kabani, Malek, Finamore, Francesco, Xu, Yan, Lee, Virginia M.-Y., Lashuel, Hilal A.

Issue&Volume: 2023-05-29

Abstract: Despite the strong evidence linking the transactive response DNA-binding protein 43 (TDP-43) aggregation to the pathogenesis of frontotemporal lobar degeneration with TDP-43, amyotrophic lateral sclerosis and several neurodegenerative diseases, our knowledge of the sequence and structural determinants of its aggregation and neurotoxicity remains incomplete. Herein, we present a new method for producing recombinant full-length TDP-43 filaments that exhibit sequence and morphological features similar to those of brain-derived TDP-43 filaments. We show that TDP-43 filaments contain a β-sheet-rich helical amyloid core that is fully buried by the flanking structured domains of the protein. We demonstrate that the proteolytic cleavage of TDP-43 filaments and exposure of this amyloid core are necessary for propagating TDP-43 pathology and enhancing the seeding of brain-derived TDP-43 aggregates. Only TDP-43 filaments with exposed amyloid core efficiently seeded the aggregation of endogenous TDP-43 in cells. These findings suggest that inhibiting the enzymes mediating cleavage of TDP-43 aggregates represents a viable disease-modifying strategy to slow the progression of amyotrophic lateral sclerosis and other TDP-43 proteinopathies.

DOI: 10.1038/s41593-023-01341-4

Source: https://www.nature.com/articles/s41593-023-01341-4

期刊信息

Nature Neuroscience:《自然—神经科学》,创刊于1998年。隶属于施普林格·自然出版集团,最新IF:28.771
官方网址:https://www.nature.com/neuro/
投稿链接:https://mts-nn.nature.com/cgi-bin/main.plex