A proteomic approach to the bilirubin-induced toxicity in neuronal cells reveals a protective function of DJ-1 protein
A proteomic approach to the bilirubin-induced toxicity in neuronal cells reveals a protective function of DJ-1 protein
复制标题
DOI：
10.1002/pmic.200900579
复制
发表时间：
2010-04-01
期刊：
影响因子：
3.4
通讯作者：
Tell, Gianluca
中科院分区：
文献类型：
--
作者：
Deganuto, Marta;Cesaratto, Laura;Tell, Gianluca
非共轭胆红素（Unconjugated bilirubin， UCB）是一种强大的抗氧化剂，并通过与多种信号转导途径相互作用来调节细胞生长。虽然新生儿会出现生理性黄疸，但在严重高胆红素血症的情况下，UCB可能会产生神经毒性，导致严重的长期神经元损伤，也称为胆红素脑病。为了研究ucb诱导神经元毒性的机制，我们以人神经母细胞瘤细胞系SH-SY5Y作为体外模型系统。我们证实UCB导致细胞死亡，部分原因是氧化应激导致DNA损伤和细胞生长减少。通过蛋白质组学方法研究了细胞毒性和细胞适应UCB的机制，鉴定了参与细胞增殖、细胞内运输、蛋白质降解和氧化应激反应的差异表达蛋白。特别是，研究结果表明，暴露于UCB的细胞会产生一种适应性反应，其中涉及dj - 1，一种多功能神经保护蛋白，对细胞氧化应激稳态至关重要。本研究揭示了胆红素诱导神经毒性的机制，并可能有助于设计一种策略来预防或改善导致胆红素脑病的神经元损伤。
Unconjugated bilirubin (UCB) is a powerful antioxidant and a modulator of cell growth through the interaction with several signal transduction pathways. Although newborns develop a physiological jaundice, in case of severe hyperbilirubinemia UCB may become neurotoxic causing severe long-term neuronal damages, also known as bilirubin encephalopathy. To investigate the mechanisms of UCB-induced neuronal toxicity, we used the human neuroblastoma cell line SH-SY5Y as an in vitro model system. We verified that UCB caused cell death, in part due to oxidative stress, which leads to DNA damage and cell growth reduction. The mechanisms of cytotoxicity and cell adaptation to UCB were studied through a proteomic approach that identified differentially expressed proteins involved in cell proliferation, intracellular trafficking, protein degradation and oxidative stress response. In particular, the results indicated that cells exposed to UCB undertake an adaptive response that involves DJ-I, a multifunctional neuroprotective protein, crucial for cellular oxidative stress homeostasis. This study sheds light on the mechanisms of bilirubin-induced neurotoxicity and might help to design a strategy to prevent or ameliorate the neuronal damages leading to bilirubin encephalopathy.