The burden of trisomy 21 disrupts the proteostasis network in Down syndrome.
The burden of trisomy 21 disrupts the proteostasis network in Down syndrome.
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DOI：
10.1371/journal.pone.0176307
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Roede JR
中科院分区：
文献类型：
--
作者：
Aivazidis S;Coughlan CM;Rauniyar AK;Jiang H;Liggett LA;Maclean KN;Roede JR
唐氏综合症 (DS) 是一种由 21 号染色体三体引起的遗传性疾病。染色体数量异常有可能导致蛋白质稳态网络 (PN) 破坏和错误折叠蛋白质的积累。 DS 个体患有多种合并症，我们假设蛋白质稳态的破坏可能导致 DS 中观察到的病理学和细胞活力降低。我们的结果证实了 DS 中存在破坏的 PN，因为与细胞和小鼠模型中的整倍体对照相比，其几个元素（包括未折叠蛋白反应、分子伴侣系统和蛋白酶体降解）表现出显着变化。此外，当用促进蛋白质稳态破坏的化合物处理细胞模型时，我们观察到与对照组相比，DS 中的细胞活力水平降低。总的来说，我们的研究结果提供了 DS PN 功能障碍的细胞水平特征，并加深了对 DS 细胞生理学破坏的潜在致病机制的理解。最后，这项研究强调了设计减轻蛋白质质量控制功能障碍的治疗策略的未来潜力。
Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21. Abnormalities in chromosome number have the potential to lead to disruption of the proteostasis network (PN) and accumulation of misfolded proteins. DS individuals suffer from several comorbidities, and we hypothesized that disruption of proteostasis could contribute to the observed pathology and decreased cell viability in DS. Our results confirm the presence of a disrupted PN in DS, as several of its elements, including the unfolded protein response, chaperone system, and proteasomal degradation exhibited significant alterations compared to euploid controls in both cell and mouse models. Additionally, when cell models were treated with compounds that promote disrupted proteostasis, we observed diminished levels of cell viability in DS compared to controls. Collectively our findings provide a cellular-level characterization of PN dysfunction in DS and an improved understanding of the potential pathogenic mechanisms contributing to disrupted cellular physiology in DS. Lastly, this study highlights the future potential of designing therapeutic strategies that mitigate protein quality control dysfunction.