Paul Flechsig Institute of Brain Research, Medical Faculty, Universität Leipzig, Leipzig, Germany.
Felix Bloch Institute for Solid State Physics, Faculty of Physics and Earth Sciences, Universität Leipzig, Leipzig, Germany.
Acta Neuropathol Commun. 2021 Mar 22;9(1):47. doi: 10.1186/s40478-021-01145-2.
Iron is essential for neurons and glial cells, playing key roles in neurotransmitter synthesis, energy production and myelination. In contrast, high concentrations of free iron can be detrimental and contribute to neurodegeneration, through promotion of oxidative stress. Particularly in Parkinson's disease (PD) changes in iron concentrations in the substantia nigra (SN) was suggested to play a key role in degeneration of dopaminergic neurons in nigrosome 1. However, the cellular iron pathways and the mechanisms of the pathogenic role of iron in PD are not well understood, mainly due to the lack of quantitative analytical techniques for iron quantification with subcellular resolution. Here, we quantified cellular iron concentrations and subcellular iron distributions in dopaminergic neurons and different types of glial cells in the SN both in brains of PD patients and in non-neurodegenerative control brains (Co). To this end, we combined spatially resolved quantitative element mapping using micro particle induced X-ray emission (µPIXE) with nickel-enhanced immunocytochemical detection of cell type-specific antigens allowing to allocate element-related signals to specific cell types. Distinct patterns of iron accumulation were observed across different cell populations. In the control (Co) SNc, oligodendroglial and astroglial cells hold the highest cellular iron concentration whereas in PD, the iron concentration was increased in most cell types in the substantia nigra except for astroglial cells and ferritin-positive oligodendroglial cells. While iron levels in astroglial cells remain unchanged, ferritin in oligodendroglial cells seems to be depleted by almost half in PD. The highest cellular iron levels in neurons were located in the cytoplasm, which might increase the source of non-chelated Fe, implicating a critical increase in the labile iron pool. Indeed, neuromelanin is characterised by a significantly higher loading of iron including most probable the occupancy of low-affinity iron binding sites. Quantitative trace element analysis is essential to characterise iron in oxidative processes in PD. The quantification of iron provides deeper insights into changes of cellular iron levels in PD and may contribute to the research in iron-chelating disease-modifying drugs.
铁对于神经元和神经胶质细胞都是必不可少的，在神经递质合成、能量产生和髓鞘形成中发挥关键作用。相比之下，高浓度的游离铁可能是有害的，并通过促进氧化应激导致神经退行性变。特别是在帕金森病 (PD) 中，纹状体黑质 (SN) 中铁浓度的变化被认为在黑质 1 中多巴胺能神经元的退化中起关键作用。然而，细胞内铁途径和铁在 PD 中的致病作用的机制尚未完全清楚，主要是因为缺乏用于定量分析具有亚细胞分辨率的铁定量的分析技术。在这里，我们使用微粒子诱导 X 射线发射 (µPIXE) 进行空间分辨定量元素映射，并结合镍增强免疫细胞化学检测细胞类型特异性抗原，以将元素相关信号分配给特定的细胞类型，从而在 PD 患者和非神经退行性控制脑 (Co) 的 SN 中定量测定多巴胺能神经元和不同类型神经胶质细胞中的细胞内铁浓度和亚细胞铁分布。结果显示，在对照组 (Co) SNc 中，少突胶质细胞和星形胶质细胞的细胞内铁浓度最高，而在 PD 中，除了星形胶质细胞和铁蛋白阳性的少突胶质细胞外，SN 中的大多数细胞类型的铁浓度均增加。虽然星形胶质细胞中的铁水平保持不变，但 PD 中的铁蛋白似乎减少了近一半。神经元中最高的细胞内铁水平位于细胞质中，这可能会增加非螯合 Fe 的来源，暗示不稳定铁池的显著增加。事实上，神经黑色素的特征是铁的负载明显增加，包括最可能占据低亲和力铁结合位点。痕量元素分析对于研究 PD 中的氧化过程中铁的特性至关重要。铁的定量分析为 PD 中细胞内铁水平的变化提供了更深入的了解，并可能为铁螯合疾病修饰药物的研究做出贡献。
