Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome
Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome
复制标题
DOI：
10.1016/j.celrep.2018.04.041
复制
发表时间：
2018-05-08
期刊：
影响因子：
8.8
通讯作者：
Iben, Sebastian
中科院分区：
文献类型：
--
作者：
Alupei, Marius Costel;Maity, Pallab;Iben, Sebastian
生长迟缓和神经退行性变是早老性疾病柯凯因综合征（CS）的标志。Cockayne综合征蛋白参与了核糖体生物发生的关键步骤，即RNA聚合酶I的转录。在这里，我们确定了一种源于RNA聚合酶I转录紊乱的机制，该机制影响核糖体的翻译保真度，从而产生错误折叠的蛋白质。在CS患者的细胞中，错误折叠的蛋白质被升高的活性氧（ROS）氧化，引发未折叠的蛋白质反应，抑制RNA聚合酶I的转录。这种病理机制可以通过添加药物伴侣来破坏，这提示了一种治疗CS的策略。此外，在小鼠CS模型中未观察到这种蛋白质稳态的丧失。
Retarded growth and neurodegeneration are hallmarks of the premature aging disease Cockayne syndrome (CS). Cockayne syndrome proteins take part in the key step of ribosomal biogenesis, transcription of RNA polymerase I. Here, we identify a mechanism originating from a disturbed RNA polymerase I transcription that impacts translational fidelity of the ribosomes and consequently produces misfolded proteins. In cells from CS patients, the misfolded proteins are oxidized by the elevated reactive oxygen species (ROS) and provoke an unfolded protein response that represses RNA polymerase I transcription. This pathomechanism can be disrupted by the addition of pharmacological chaperones, suggesting a treatment strategy for CS. Additionally, this loss of proteostasis was not observed in mouse models of CS.