Cystatin C protects neuronal cells against mutant copper-zinc superoxide dismutase-mediated toxicity.
Cystatin C protects neuronal cells against mutant copper-zinc superoxide dismutase-mediated toxicity.
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DOI：
10.1038/cddis.2014.459
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发表时间：
2014-10-30
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种以运动神经元选择性进行性丧失为特征的神经退行性疾病。半胱氨酸蛋白酶抑制剂C（CysC）是一种内源性半胱氨酸蛋白酶抑制剂，是在散发性ALS的脊髓运动神经元中观察到的布尼纳体的主要蛋白组分，并且在ALS患者的脑脊液中减少。尽管CysC在ALS中显著沉积，但CysC在中枢神经系统中的作用仍然未知。在这里，我们确定了CysC对ALS连锁突变体铜/锌-超氧化物歧化酶（SOD 1）介导的毒性的神经保护活性。我们发现，外源性添加CysC保护神经元细胞，包括原代培养的运动神经元。此外，CysC的神经保护特性依赖于两个不同途径的协同激活：通过AMPK-mTOR途径诱导自噬和抑制组织蛋白酶B。此外，外源性添加的CysC被转导到细胞中，并在氧化应激条件下聚集在胞质溶胶中，这意味着CysC的神经保护活性和Bunina体形成之间的关系。这些数据表明CysC是一种内源性神经保护剂，靶向运动神经元中的CysC可能为ALS提供新的治疗策略。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. Cystatin C (CysC), an endogenous cysteine protease inhibitor, is a major protein component of Bunina bodies observed in the spinal motor neurons of sporadic ALS and is decreased in the cerebrospinal fluid of ALS patients. Despite prominent deposition of CysC in ALS, the roles of CysC in the central nervous system remain unknown. Here, we identified the neuroprotective activity of CysC against ALS-linked mutant Cu/Zn-superoxide dismutase (SOD1)-mediated toxicity. We found that exogenously added CysC protected neuronal cells including primary cultured motor neurons. Moreover, the neuroprotective property of CysC was dependent on the coordinated activation of two distinct pathways: autophagy induction through AMPK-mTOR pathway and inhibition of cathepsin B. Furthermore, exogenously added CysC was transduced into the cells and aggregated in the cytosol under oxidative stress conditions, implying a relationship between the neuroprotective activity of CysC and Bunina body formation. These data suggest CysC is an endogenous neuroprotective agent and targeting CysC in motor neurons may provide a novel therapeutic strategy for ALS.
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影响因子：
9.9
作者：
Hirano, A
通讯作者：
Hirano, A
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
6.1
作者：
Kim, Jean;Kim, Tae-Youn;Koh, Jae-Young
通讯作者：
Koh, Jae-Young
影响因子：
6.1
作者：
Dave, KR;Raval, AP;Pérez-Pinzón, MA
通讯作者：
Pérez-Pinzón, MA
影响因子：
2.2
作者：
AIDA, Y;PABST, MJ
通讯作者：
PABST, MJ