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Interactome screening of C9orf72 dipeptide repeats reveals VCP sequestration and functional impairment by polyGA
Brain ( IF 14.5 ) Pub Date : 2021-08-11 , DOI: 10.1093/brain/awab300
Janja Božič 1 , Helena Motaln 1 , Anja Pucer Janež 1 , Lara Markič 1 , Priyanka Tripathi 2 , Alfred Yamoah 2 , Eleonora Aronica 3 , Youn-Bok Lee 4 , Raphael Heilig 5 , Roman Fischer 5 , Andrew J Thompson 6 , Anand Goswami 2 , Boris Rogelj 1, 7, 8
Affiliation  

Repeat expansions in the C9orf72 gene are a common cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, two devastating neurodegenerative disorders. One of the proposed mechanisms of GGGGCC repeat expansion is their translation into non-canonical dipeptide repeats, which can then accumulate as aggregates and contribute to these pathologies. There are five different dipeptide repeat proteins (polyGA, polyGR, polyPR, polyPA and polyGP), some of which are known to be neurotoxic. In the present study, we used BioID2 proximity labelling to identify the interactomes of all five dipeptide repeat proteins consisting of 125 repeats each. We identified 113 interacting partners for polyGR, 90 for polyGA, 106 for polyPR, 25 for polyPA and 27 for polyGP. Gene Ontology enrichment analysis of the proteomic data revealed that these target interaction partners are involved in a variety of functions, including protein translation, signal transduction pathways, protein catabolic processes, amide metabolic processes and RNA-binding. Using autopsy brain tissue from patients with C9orf72 expansion complemented with cell culture analysis, we evaluated the interactions between polyGA and valosin containing protein (VCP). Functional analysis of this interaction revealed sequestration of VCP with polyGA aggregates, altering levels of soluble valosin-containing protein. VCP also functions in autophagy processes, and consistent with this, we observed altered autophagy in cells expressing polyGA. We also observed altered co-localization of polyGA aggregates and p62 in cells depleted of VCP. All together, these data suggest that sequestration of VCP with polyGA aggregates contributes to the loss of VCP function, and consequently to alterations in autophagy processes in C9orf72 expansion disorders.

中文翻译:

C9orf72 二肽重复序列的相互作用筛选揭示了 polyGA 对 VCP 的螯合和功能损害

C9orf72 基因的重复扩增是肌萎缩侧索硬化和额颞叶变性的常见原因,这两种破坏性神经退行性疾病。提出的 GGGGCC 重复扩增机制之一是将它们翻译成非规范二肽重复,然后可以聚集成聚集体并促成这些病理。有五种不同的二肽重复蛋白(polyGA、polyGR、polyPR、polyPA 和 polyGP),其中一些已知具有神经毒性。在本研究中,我们使用 BioID2 邻近标记来识别由 125 个重复组成的所有五种二肽重复蛋白的相互作用组。我们确定了 polyGR 的 113 个相互作用伙伴,polyGA 的 90 个,polyPR 的 106 个,polyPA 的 25 个和 polyGP 的 27 个。蛋白质组数据的基因本体富集分析表明,这些目标相互作用伙伴参与多种功能,包括蛋白质翻译、信号转导途径、蛋白质分解代谢过程、酰胺代谢过程和 RNA 结合。使用来自 C9orf72 扩增患者的尸检脑组织并辅以细胞培养分析,我们评估了 polyGA 和含有 valosin 的蛋白质 (VCP) 之间的相互作用。这种相互作用的功能分析揭示了 VCP 与 polyGA 聚集体的隔离,改变了可溶性含 valosin 蛋白的水平。VCP 在自噬过程中也起作用,与此一致,我们观察到表达 polyGA 的细胞中自噬发生改变。我们还观察到在耗尽 VCP 的细胞中 polyGA 聚集体和 p62 的共定位发生了改变。全部一起,
更新日期:2021-08-11
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