Pathological mechanisms in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, are still poorly understood. One subset of familial ALS cases is caused by mutations in the metallo-enzyme copper-zinc superoxide dismutase (SOD1), increasing the susceptibility of the SOD1 protein to form insoluble intracellular aggregates. Here, we employed synchrotron radiation-based Fourier transform infrared spectroscopy and microscopy to investigate brainstem cross-sections from the transgenic hSOD1 G93A rat model of ALS that overexpresses human-mutated SOD1. We compared the biomacromolecular organic composition in brainstem tissue cross-sections of ALS rats and their non-transgenic littermates (NTg). We demonstrate that the proteins and especially their antiparallel β-sheet structure significantly differed in all three regions: the facial nucleus (FN), the gigantocellular reticular nucleus (GRN) and the trigeminal motor nucleus (TMN) in the brainstem tissue of ALS rats. The protein levels varied between different brainstem areas, with the highest concentration observed in the region of the FN in the brainstem tissue of NTg animals. Furthermore, the concentration of lipids and esters was significantly decreased in the TMN and FN of ALS animals. A similar pattern was detected for choline and phosphate assigned to nucleic acids with the highest concentrations in the FN of NTg animals. The spectroscopic analysis showed significant differences in phosphates, amide and lipid structure in the FN of NTg animals in comparison with the same area of ALS rats. These results show that the hG93A SOD1 mutation causes metabolic cellular changes and point to a link between bioorganic composition and hallmarks of protein aggregation.

中文翻译：

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肌萎缩性侧索硬化的hSOD1 G93A大鼠模型脑干的基于同步辐射的FTIR光谱显微镜。

肌萎缩性侧索硬化症（ALS）这种致命的神经退行性疾病的病理机制仍知之甚少。家族性ALS病例的一个子集是由金属酶铜锌超氧化物歧化酶（SOD1）的突变引起的，从而增加了SOD1蛋白形成不溶性细胞内聚集体的敏感性。在这里，我们采用了基于同步辐射的傅立叶变换红外光谱和显微镜技术，研究了过表达人突变型SOD1的ALS转基因hSOD1 G93A大鼠模型的脑干横断面。我们比较了ALS大鼠及其非转基因同窝动物（NTg）在脑干组织横截面中的生物大分子有机组成。我们证明了蛋白质，尤其是它们的反平行β-折叠结构在所有三个区域中均显着不同：ALS大鼠脑干组织中的面部核（FN），大细胞网状核（GRN）和三叉神经运动核（TMN）。蛋白质水平在不同的脑干区域之间变化，在NTg动物的脑干组织中的FN区域中观察到最高浓度。此外，ALS动物的TMN和FN中脂质和酯的浓度显着降低。在NTg动物的FN中，检测到分配给具有最高浓度核酸的胆碱和磷酸盐的模式相似。光谱分析显示，与相同面积的ALS大鼠相比，NTg动物的FN的磷酸盐，酰胺和脂质结构有显着差异。