タンパク質S-ニトロシル化が関与するシナプス障害と神経変性疾患

抄録

Growing evidence suggests that synaptic dysfunction, rather than neuronal loss, correlates most strongly to cognitive decline in neurodegenerative disorders, including Alzheimer’s disease and Lewy body dementia. The potential contributing factors to cognitive impairment likely include environmental risk factors. For examples, chronic exposure to environmental agents such as fine particulate matter in polluted air, as well as agricultural chemicals, such as paraquat and rotenone, is associated with increased risk of neurodegenerative diseases. In these cases, environmental toxins can engender excessive production of reactive oxygen/ nitrogen species (ROS/RNS) including nitric oxide (NO)-related species, thereby contributing to synaptic damage. NO-related species can react with critical cysteine residues (more properly, thiolate anion) of target proteins to form the posttranslational modification known as S-nitrosylation, modulating the functional activity of many signaling proteins. Moreover, we demonstrated that S-nitrosylation signaling spreads predominantly through transnitrosylation reactions, involving a transfer of an NO group between multiple proteins. Collectively, these aberrant transnitrosylation/S-nitrosylation pathways trigger mitochondrial dysfunction, transcriptional alterations, neuroinflammation, and protein aggregation, eventually leading to synaptic damage and neuronal loss. In this presentation, we will highlight our recent findings on aberrant transnitrosylation/S-nitrosylation pathways that contribute to the etiology of neurodegenerative disorders.