自噬
愤怒(情绪)
氧化应激
自噬相关蛋白13
生物
糖基化
炎症
小胶质细胞
免疫学
活性氧
糖基化终产物
一氧化氮
内科学
作者
Gunnar Gottschalk,Daniel Peterson,Konstance Knox,Marco Maynard,Ryan J. Whelan,Avik Roy
标识
DOI:10.1016/j.mcn.2022.103731
摘要
Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a multisystem illness characterized by extreme muscle fatigue associated with pain, neurocognitive impairment, and chronic inflammation. Despite intense investigation, the molecular mechanism of this disease is still unknown. Here we demonstrate that autophagy-related protein ATG13 is strongly upregulated in the serum of ME/CFS patients, indicative of impairment in the metabolic events of autophagy. A Thioflavin T-based protein aggregation assay, array screening for autophagy-related factors, densitometric analyses, and confirmation with ELISA revealed that the level of ATG13 was strongly elevated in serum samples of ME/CFS patients compared to age-matched controls. Moreover, our microglia-based oxidative stress response experiments indicated that serum samples of ME/CFS patients evoke the production of reactive oxygen species (ROS) and nitric oxide in human HMC3 microglial cells, whereas neutralization of ATG13 strongly diminishes the production of ROS and NO, suggesting that ATG13 plays a role in the observed stress response in microglial cells. Finally, an in vitro ligand binding assay provided evidence that ATG13 employs the Receptor for Advanced Glycation End-products (RAGE) to stimulate ROS in microglial cells. Collectively, our results suggest that an impairment of autophagy following the release of ATG13 into serum could be a pathological signal in ME/CFS. • Serum samples of ME/CFS patients display a higher propensity of protein aggregation indicating potential impairment of protein degradation mechanism. • An elevated level of ATG13 in serum of ME/CFS patients suggests an autophagy impairment as a molecular mechanism in the disease. • Serum-derived ATG13 is phosphorylated, binds to the Receptor for Advanced Glycan End product (RAGE), and induces the production of reactive oxygen species (ROS) and nitric oxide (NO) in cultured microglial cells.
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