Senescence marker protein 30 deficiency increases Parkinson's pathology by impairing astrocyte activation
Senescence marker protein 30 deficiency increases Parkinson's pathology by impairing astrocyte activation
复制标题
DOI：
10.1016/j.neurobiolaging.2012.10.008
复制
发表时间：
2013-04-01
影响因子：
4.2
通讯作者：
Lee, Jaewon
中科院分区：
文献类型：
--
作者：
Kim, Hyun Soo;Son, Tae Gen;Lee, Jaewon
衰老标记蛋白30（SMP 30）是近年来发现的一种与维生素C（VC）生物合成有关的蛋白质。因此，SMP 30的抗氧化特性被认为是由其β-内酯酶功能介导的。然而，尚未在神经退行性疾病模型中研究不依赖于VC生物合成的SMP 30缺乏的病理影响。在本研究中，我们评估了SMP 30缺陷对SMP 30敲除（KO）小鼠中帕金森病（PD）的影响。用1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）处理补充VC的野生型和SMP 30 KO小鼠。我们的研究结果表明，MPTP诱导的多巴胺能神经元的损失和运动功能障碍的SMP 30基因敲除小鼠更显着。MPTP处理的SMP 30 KO小鼠中活性氧生成和小胶质细胞活化更高。然而，SMP 30缺陷减轻MPTP诱导的星形胶质细胞活化和胶质源性神经营养因子的产生。从野生型和SMP 30 KO小鼠中回收的星形胶质细胞的培养物显示，SMP 30缺陷通过阻断细胞外信号调节激酶途径来消除1-甲基-4-苯基-吡啶诱导的星形胶质细胞活化。综上所述，我们的研究结果首次表明，SMP 30缺乏会增加PD的严重程度，并表明SMP 30在响应神经变性的保护性星形胶质细胞活化中具有有益作用。目前的研究表明，调节星形胶质细胞SMP 30可能是治疗PD的一个有前途的靶点。(C)2013 Elsevier Inc. All rights reserved.
Senescence marker protein 30 (SMP30) was recently identified as gluconolactonase, which is involved in vitamin C (VC) biosynthesis. Therefore, the antioxidant property of SMP30 is thought to be mediated by its gluconolactonase function. However, pathologic effects of SMP30 deficiency independent of VC biosynthesis have not been studied in models of neurodegenerative diseases. In the present study, we evaluated the effect of SMP30 deficiency on Parkinson's disease (PD) in SMP30 knockout (KO) mice. Wild type and SMP30 KO mice supplemented with VC were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our results showed that MPTP-induced dopaminergic neuronal loss and motor function impairment were more significant in the SMP30 KO mice. Reactive oxygen species generation and microglia activation were higher in MPTP-treated SMP30 KO mice. However, SMP30 deficiency mitigated MPTP-induced astrocyte activation and glia-derived neurotrophic factor production. Cultures of astrocytes recovered from wild type and SMP30 KO mice revealed that SMP30 deficiency abolished 1-methyl-4-phenyl-pyridinium-induced astroglial activation by blocking the extracellular signal-regulated kinase pathway. Taken together, our findings demonstrate for the first time that SMP30 deficiency increases the severity of PD and suggest a beneficial role of SMP30 in protective astrocyte activation in response to neurodegeneration. The present study shows that modulation of astrocytic SMP30 can be a promising target for treating PD. (C) 2013 Elsevier Inc. All rights reserved.