School of Medical Science, Griffith University, Southport, QLD 4222, Australia.
Centre for Motor Neuron Disease Research, Macquarie University, Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Sydney, NSW 2109, Australia.
Cells. 2019 Feb 19;8(2):179. doi: 10.3390/cells8020179.
The formation of cytotoxic intracellular protein aggregates is a pathological signature of multiple neurodegenerative diseases. The principle aggregating protein in Parkinson's disease (PD) and atypical Parkinson's diseases is α-synuclein (α-syn), which occurs in neural cytoplasmic inclusions. Several factors have been found to trigger α-syn aggregation, including raised calcium, iron, and copper. Transcriptional inducers have been explored to upregulate expression of endogenous metal-binding proteins as a potential neuroprotective strategy. The vitamin-D analogue, calcipotriol, induced increased expression of the neuronal vitamin D-dependent calcium-binding protein, calbindin-D28k, and this significantly decreased the occurrence of α-syn aggregates in cells with transiently raised intracellular free Ca, thereby increasing viability. More recently, the induction of endogenous expression of the Zn and Cu binding protein, metallothionein, by the glucocorticoid analogue, dexamethasone, gave a specific reduction in Cu-dependent α-syn aggregates. Fe accumulation has long been associated with PD. Intracellularly, Fe is regulated by interactions between the Fe storage protein ferritin and Fe transporters, such as poly(C)-binding protein 1. Analysis of the transcriptional regulation of Fe binding proteins may reveal potential inducers that could modulate Fe homoeostasis in disease. The current review highlights recent studies that suggest that transcriptional inducers may have potential as novel mechanism-based drugs against metal overload in PD.
细胞毒性细胞内蛋白聚集体的形成是多种神经退行性疾病的病理特征。帕金森病（PD）和非典型帕金森病的主要聚集蛋白是α-突触核蛋白（α-syn），它存在于神经细胞质内包涵体中。已经发现了几种触发α-syn 聚集的因素，包括钙、铁和铜的升高。已经探索了转录诱导剂来上调内源性金属结合蛋白的表达，作为一种潜在的神经保护策略。维生素 D 类似物，钙泊三醇，诱导神经元维生素 D 依赖性钙结合蛋白，钙结合蛋白-D28k 的表达增加，这显著降低了瞬时升高细胞内游离 Ca 时细胞中 α-syn 聚集体的发生，从而提高了细胞活力。最近，糖皮质激素类似物地塞米松诱导内源性锌和铜结合蛋白金属硫蛋白的表达，特异性减少 Cu 依赖性 α-syn 聚集体。铁的积累长期以来与 PD 有关。细胞内，铁通过铁储存蛋白铁蛋白和铁转运蛋白（如多聚（C）结合蛋白 1）之间的相互作用来调节。对铁结合蛋白的转录调控分析可能揭示潜在的诱导剂，这些诱导剂可能在疾病中铁稳态的调节中发挥作用。本综述强调了最近的研究表明，转录诱导剂可能具有作为新型基于机制的药物的潜力，用于治疗 PD 中的金属过载。
