Gonzalez-Alcocer Alfredo, Gopar-Cuevas Yareth, Soto-Dominguez Adolfo, Castillo-Velazquez Uziel, de Jesus Loera-Arias Maria, Saucedo-Cardenas Odila, de Oca-Luna Roberto Montes, Garcia-Garcia Aracely, Rodriguez-Rocha Humberto
Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León 64460, Mexico.
Departamento de Inmunología Veterinaria, Facultad de Medicina Veterinaria y Zootecnia, Universidad Autónoma de Nuevo León, Escobedo, Nuevo León 66050, Mexico.
Neurotoxicology. 2023 Mar;95:181-192. doi: 10.1016/j.neuro.2023.02.002. Epub 2023 Feb 11.
The environment, containing pollutants, toxins, and transition metals (copper, iron, manganese, and zinc), plays a critical role in neurodegenerative disease development. Copper occupational exposure increases Parkinson's disease (PD) risk. Previously, we determined the mechanisms by which copper induces dopaminergic cell death in vitro. The copper transporter protein 1 (Ctr1) overexpression led to intracellular glutathione depletion potentiating caspase-3 mediated cell death; oxidative stress was primarily cytosolic, and Nrf2 was upregulated mediating an antioxidant response; and protein ubiquitination, AMPK-Ulk1 signaling, p62, and Atg5-dependent autophagy were increased as a protective mechanism. However, the effect of chronic copper exposure on the neurodegenerative process has not been explored in vivo. We aimed to elucidate whether prolonged copper treatment reproduces PD features and mechanisms during aging. Throughout 40 weeks, C57BL/6J male mice were treated with copper at 0, 100, 250, and 500 ppm in the drinking water. Chronic copper exposure altered motor function and induced dopaminergic neuronal loss, astrocytosis, and microgliosis in a dose-dependent manner. α-Synuclein accumulation and aggregation were increased in response to copper, and the proteasome and autophagy alterations, previously observed in vitro, were confirmed in vivo, where protein ubiquitination, AMPK phosphorylation, and the autophagy marker LC3-II were also increased by copper exposure. Finally, nitrosative stress was induced by copper in a concentration-dependent fashion, as evidenced by increased protein nitration. To our knowledge, this is the first study combining chronic copper exposure and aging, which may represent an in vivo model of non-genetic PD and help to assess potential prophylactic and therapeutic approaches. DATA AVAILABILITY: The data underlying this article are available in the article.
含有污染物、毒素和过渡金属（铜、铁、锰和锌）的环境在神经退行性疾病的发展中起着关键作用。职业性铜暴露会增加患帕金森病（PD）的风险。此前，我们确定了铜在体外诱导多巴胺能细胞死亡的机制。铜转运蛋白1（Ctr1）的过表达导致细胞内谷胱甘肽耗竭，增强了半胱天冬酶-3介导的细胞死亡；氧化应激主要在细胞质中，核因子E2相关因子2（Nrf2）上调介导抗氧化反应；蛋白质泛素化、AMPK-Ulk1信号传导、p62和Atg5依赖性自噬增加作为一种保护机制。然而，慢性铜暴露对神经退行性过程的影响尚未在体内进行研究。我们旨在阐明长期铜处理是否会在衰老过程中重现PD的特征和机制。在40周的时间里，给C57BL/6J雄性小鼠饮用含0、100、250和500 ppm铜的水。慢性铜暴露以剂量依赖性方式改变运动功能，并诱导多巴胺能神经元丢失、星形细胞增生和小胶质细胞增生。α-突触核蛋白的积累和聚集因铜而增加，先前在体外观察到的蛋白酶体和自噬改变在体内得到证实，铜暴露也增加了蛋白质泛素化、AMPK磷酸化和自噬标志物LC3-II。最后，铜以浓度依赖性方式诱导亚硝化应激，蛋白质硝化增加证明了这一点。据我们所知，这是第一项将慢性铜暴露与衰老相结合的研究，这可能代表一种非遗传性PD的体内模型，并有助于评估潜在的预防和治疗方法。数据可用性：本文的基础数据可在文章中获取。
