RTP801 is a critical factor in the neurodegeneration process of A53T-synuclein in a mouse model of Parkinson's disease under chronic restraint stress
RTP801 is a critical factor in the neurodegeneration process of A53T-synuclein in a mouse model of Parkinson's disease under chronic restraint stress
复制标题
RTP801是慢性束缚应激下帕金森病小鼠模型中A53T-突触核蛋白神经变性过程的关键因素
DOI：
10.1111/bph.14091
复制
发表时间：
2018
影响因子：
7.3
通讯作者：
Chen Nai-Hong
中科院分区：
文献类型：
--
作者：
Zhang Zhao;Chu Shi-Feng;Wang Sha-Sha;Jiang Yi-Na;Gao Yan;Yang Peng-Fei;Ai Qi-Di;Chen Nai-Hong
背景与目的近年来，帕金森病的发病率有向年轻化人群转移的趋势，这与现代社会不断增加的压力源有关。然而，这种关系仍然模糊不清。在这里，我们研究了压力的贡献和这种变化的机制。实验方法：采用慢性约束应激（CRS）对10月龄α -突触核蛋白A53T小鼠进行慢性约束应激（CRS）治疗，模拟PD敏感个体持续应激刺激。评估PD样行为测试和病理改变。分化后的PC12‐A53T细胞用皮质酮体外处理。我们采用Western blot、microRNA表达分析、免疫荧光染色、双荧光素酶报告试验和HPLC电化学检测来评估应激处理后的细胞和分子网络。体内用立体定向注射shRNA慢病毒来证实体外结果。关键结果RTP801蛋白由DNA损伤诱导转录物4编码，并在CRS处理后的黑质多巴胺能神经元中特异性升高。RTP801转录后受到miR - 7下调的抑制。RTP801通过抑制蛋白酶体降解而延迟周转也是其含量高的原因之一。升高的RTP801阻断了自噬，从而增加了寡聚α‐突触核蛋白的积累，加重了内质网应激。在此过程中，抑制RTP801可减轻神经退行性变的症状。结论和意义srtp801是治疗PD的一个有希望的靶点，特别是对于生活在社会压力下的PD敏感患者。RTP801的下调可以抑制PD早期发病的趋势。
Background and PurposeRecently, the incidence of Parkinson's disease has shown a tendency to move to a younger population, linked to the constantly increasing stressors of modern society. However, this relationship remains obscure. Here, we have investigated the contribution of stress and the mechanisms underlying this change.Experimental ApproachTen‐month‐old α‐synuclein A53T mice, a model of Parkinson's disease (PD), were treated with chronic restraint stress (CRS) to simulate a PD‐sensitive person with constant stress stimulation. PD‐like behavioural tests and pathological changes were evaluated. Differentiated PC12‐A53T cells were treated with corticosteronein vitro. We used Western blot, microRNA expression analysis, immunofluorescence staining, dual luciferase reporter assay and HPLC electrochemical detection to assess cellular and molecular networks after stress treatment.In vivo,stereotaxic injection of shRNA lentivirus was used to confirm ourin vitroresults.Key ResultsThe protein RTP801 is encoded by DNA‐damage‐inducible transcript 4, and it was specifically increased in dopaminergic neurons of the substantia nigra after CRS treatment. RTP801 was post‐transcriptionally inhibited by the down‐regulation of miR‐7. Delayed turnover of RTP801, through the inhibition of proteasome degradation also contributed to its high content. Elevated RTP801 blocked autophagy, thus increasing accumulation of oligomeric α‐synuclein and aggravating endoplasmic reticulum stress. RTP801 inhibition alleviated the symptoms of neurodegeneration during this process.Conclusions and ImplicationsRTP801 is a promising target for the treatment of PD, especially for PD‐sensitive patients who live under increased social pressure. Down‐regulation of RTP801 could inhibit the current tendency to an earlier onset of PD.