In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment.
In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment.
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DOI：
10.1016/j.cell.2017.12.030
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发表时间：
2018-02-08
期刊：
影响因子：
64.5
通讯作者：
Fernández-Busnadiego R
中科院分区：
文献类型：
--
作者：
Guo Q;Lehmer C;Martínez-Sánchez A;Rudack T;Beck F;Hartmann H;Pérez-Berlanga M;Frottin F;Hipp MS;Hartl FU;Edbauer D;Baumeister W;Fernández-Busnadiego R
蛋白质聚集和泛素-蛋白酶体系统的功能障碍是许多神经退行性疾病的标志。在这里，我们解决了这些现象之间的难以捉摸的联系，采用冷冻电子断层扫描，以高分辨率解剖完整的神经元内的蛋白质聚集体的分子结构。我们专注于聚-甘氨酸-丙氨酸（GA）聚集体的异常翻译C9 orf 72，肌萎缩侧索硬化症和额颞叶痴呆症的最常见的遗传原因扩大GGGGCC重复。我们发现，聚-GA聚集体由密集包装的扭曲的丝带，招募众多的26 S蛋白酶体复合物，而其他大分子在很大程度上被排除在外。接近聚GA带稳定的26 S蛋白酶体的瞬时底物加工构象，表明停滞降解。因此，聚-GA聚集体可能通过驱动大部分细胞蛋白酶体的积累和功能损害而损害神经元蛋白质稳态。
Protein aggregation and dysfunction of the ubiquitin-proteasome system are hallmarks of many neurodegenerative diseases. Here we address the elusive link between these phenomena employing cryo-electron tomography to dissect the molecular architecture of protein aggregates within intact neurons at high resolution. We focus on the poly-Gly-Ala (GA) aggregates resulting from aberrant translation of an expanded GGGGCC repeat in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. We find that poly-GA aggregates consist of densely packed twisted ribbons that recruit numerous 26S proteasome complexes, while other macromolecules are largely excluded. Proximity to poly-GA ribbons stabilizes a transient substrate-processing conformation of the 26S proteasome, suggesting stalled degradation. Thus, poly-GA aggregates may compromise neuronal proteostasis by driving the accumulation and functional impairment of a large fraction of cellular proteasomes.
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影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
影响因子：
7.3
作者：
De Smet, Frederik;Rubio, Mirian Saiz;Rousseau, Frederic
通讯作者：
Rousseau, Frederic
影响因子：
46.9
作者：
Dantuma, NP;Lindsten, K;Masucci, MG
通讯作者：
Masucci, MG
影响因子：
64.5
作者：
Baeuerlein, Felix J. B.;Saha, Itika;Fernandez-Busnadiego, Ruben
通讯作者：
Fernandez-Busnadiego, Ruben
影响因子：
16.2
作者：
DeJesus-Hernandez M;Mackenzie IR;Boeve BF;Boxer AL;Baker M;Rutherford NJ;Nicholson AM;Finch NA;Flynn H;Adamson J;Kouri N;Wojtas A;Sengdy P;Hsiung GY;Karydas A;Seeley WW;Josephs KA;Coppola G;Geschwind DH;Wszolek ZK;Feldman H;Knopman DS;Petersen RC;Miller BL;Dickson DW;Boylan KB;Graff-Radford NR;Rademakers R
通讯作者：
Rademakers R