CHIP protects against MPP(+)/MPTP-induced damage by regulating Drp1 in two models of Parkinson's disease.
CHIP protects against MPP(+)/MPTP-induced damage by regulating Drp1 in two models of Parkinson's disease.
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CHIP 通过调节两种帕金森病模型中的 Drp1 来防止 MPP /MPTP 引起的损伤
DOI：
10.18632/aging.202389
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发表时间：
2021-01-02
期刊：
影响因子：
--
通讯作者：
Xu Y
中科院分区：
文献类型：
--
作者：
Hu Z;Mao C;Wang H;Zhang Z;Zhang S;Luo H;Tang M;Yang J;Yuan Y;Wang Y;Liu Y;Fan L;Zhang Q;Yao D;Liu F;Schisler JC;Shi C;Xu Y
线粒体功能障碍与帕金森病（PD）的发病机制有关。hsp70相互作用蛋白（CHIP）的羧基末端是线粒体动力学的关键调节因子，CHIP的突变或其表达缺陷与多种神经系统疾病有关。本研究探讨了CHIP在细胞和小鼠PD模型中的保护作用。在SH-SY5Y细胞系中，CHIP的过表达提高了细胞活力，并增加了1-甲基-4-苯基吡啶（MPP+）处理后的ATP水平。为了在动物模型中实现CHIP过表达，我们向小鼠静脉注射AAV/BBB，这是一种新的腺相关病毒血清型，具有增强的穿越血脑屏障的能力。我们也培育了在神经组织中过度表达CHIP的基因敲入小鼠。我们的研究结果表明，CHIP在小鼠中的过表达抑制了1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的损伤，包括运动障碍、运动协调和自发运动活动，以及多巴胺能神经元的丧失。体外和体内实验表明，过表达CHIP可抑制PD模型中Drp1的病理升高，提示CHIP可调节Drp1降解，减轻MPP+/ mptp诱导的损伤。我们认为CHIP在MPP+/ mptp诱导的PD模型中具有保护作用。我们的实验进一步揭示了CHIP维持线粒体的完整性。
Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson’s disease (PD). Carboxyl terminus of Hsp70-interacting protein (CHIP) is a key regulator of mitochondrial dynamics, and mutations in CHIP or deficits in its expression have been associated with various neurological diseases. This study explores the protective role of CHIP in cells and murine PD models. In SH-SY5Y cell line, overexpression of CHIP improved the cell viability and increased the ATP levels upon treatment with 1-methyl-4-phenylpyridinium (MPP+). To achieve CHIP overexpression in animal models, we intravenously injected mice with AAV/BBB, a new serotype of adeno-associated virus that features an enhanced capacity to cross the blood-brain barrier. We also generated gene knock-in mice that overexpressed CHIP in neural tissue. Our results demonstrated that CHIP overexpression in mice suppressed 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage, including movement impairments, motor coordination, and spontaneous locomotor activity, as well as loss of dopaminergic neurons. In vitro and in vivo experiments showed that overexpression of CHIP inhibited the pathological increase in Drp1 observed in the PD models, suggesting that CHIP regulates Drp1 degradation to attenuate MPP+/MPTP-induced injury. We conclude that CHIP plays a protective role in MPP+/MPTP-induced PD models. Our experiments further revealed that CHIP maintains the integrity of mitochondria.
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