Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Brazil; Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.
Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Brazil.
Biochim Biophys Acta Mol Basis Dis. 2023 Dec;1869(8):166835. doi: 10.1016/j.bbadis.2023.166835. Epub 2023 Aug 7.
Different SOD1 proteoforms are implicated## in both familial and sporadic cases of Amyotrophic Lateral Sclerosis (ALS), an aging-associated disease that affects motor neurons. SOD1 is crucial to neuronal metabolism and health, regulating the oxidative stress response and the shift between oxidative-fermentative metabolism, which is important for astrocyte-neuron metabolic cooperation. Neurons have a limited capacity to metabolize methylglyoxal (MGO), a potentially toxic side product of glycolysis. MGO is highly reactive and can readily posttranslationally modify proteins, in a reaction known as glycation, impacting their normal biology. Here, we aimed to investigate the effect of glycation on the aggregation and toxicity of human SOD1WT (hSOD1WT). Cells with deficiency in MGO metabolism showed increased levels of hSOD1WT inclusions, displaying also reduced hSOD1WT activity and viability. Strikingly, we also found that the presence of hSOD1WT in stress granules increased upon MGO treatment. The treatment of recombinant hSOD1WT with MGO resulted in the formation of SDS-stable oligomers, specially trimers, and thioflavin-T positive aggregates, which can promote cell toxicity and TDP-43 pathology. Together, our results suggest that glycation may play a still underappreciated role on hSOD1WT and TDP-43 pathologies in sporadic ALS, which could open novel perspectives for therapeutic intervention.
不同的 SOD1 蛋白异构体与家族性和散发性肌萎缩侧索硬化症（ALS）有关，这是一种与衰老相关的疾病，影响运动神经元。SOD1 对神经元代谢和健康至关重要，它调节氧化应激反应和氧化-发酵代谢之间的转变，这对星形胶质细胞-神经元代谢合作很重要。神经元代谢甲基乙二醛（MGO）的能力有限，MGO 是糖酵解的潜在毒性副产物。MGO 具有很高的反应性，可以通过一种称为糖基化的反应，在翻译后迅速修饰蛋白质，影响它们的正常生物学功能。在这里，我们旨在研究糖基化对人源 SOD1WT（hSOD1WT）聚集和毒性的影响。缺乏 MGO 代谢的细胞中 hSOD1WT 包涵体水平增加，hSOD1WT 活性和活力也降低。引人注目的是，我们还发现 MGO 处理后 hSOD1WT 在应激颗粒中的存在增加。用 MGO 处理重组 hSOD1WT 会导致 SDS 稳定的寡聚物形成，特别是三聚体和硫黄素 T 阳性聚集体，这可能会促进细胞毒性和 TDP-43 病理学。总之，我们的结果表明，糖基化可能在散发性 ALS 中对 hSOD1WT 和 TDP-43 病理学起着尚未被充分认识的作用，这为治疗干预开辟了新的视角。
