Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia; Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia.
Adv Protein Chem Struct Biol. 2023;136:339-383. doi: 10.1016/bs.apcsb.2023.02.018. Epub 2023 Apr 26.
Neurodegenerative diseases are a group of age-related disorders characterized by a chronic and progressive loss of function and/or structure of synapses, neurons, and glial cells. The etiopathogenesis of neurodegenerative diseases is characterized by a complex network of intricately intertwined pathophysiological processes that are still not fully understood. Safe and effective disease-modifying treatments are urgently needed, but still not available. Accumulating evidence suggests that gastrointestinal dyshomeostasis and microbial dysbiosis might play an important role in neurodegeneration by acting as either primary or secondary pathophysiological factors. The research on the role of microbiota in neurodegeneration is in its early phase; however, accumulating evidence suggests that dysbiosis might promote neurodegenerative diseases by disrupting mitochondrial function and inducing mitochondrial dysfunction-associated senescence (MiDAS), possibly due to bidirectional crosstalk based on the common evolutionary origin of mitochondria and bacteria. Cellular senescence is an onco-supressive homeostatic mechanism that results in an irreversible cell cycle arrest upon exposure to noxious stimuli. Senescent cells resist apoptosis via senescent cell anti-apoptotic pathways (SCAPs) and transition into a state known as senescence-associated secretory phenotype (SASP) that generates a cytotoxic proinflammatory microenvironment. Cellular senescence results in the adoption of a detrimental vicious cycle driven by dysbiosis, mitochondrial dysfunction, inflammation, and oxidative stress - a pathophysiological positive feedback loop that results in neuroinflammation and neurodegeneration. Detrimental effects of MiDAS might be prevented and abolished by mitochondria-targeted senotherapeutics, a group of drugs specifically designed to alleviate senescence by inhibiting SCAPs (senolytics), or inhibiting SASP (senomorphics).
神经退行性疾病是一组与年龄相关的疾病，其特征是突触、神经元和神经胶质细胞的慢性进行性功能和/或结构丧失。神经退行性疾病的病因发病机制以错综复杂的病理生理过程的复杂网络为特征，这些过程仍未完全了解。迫切需要安全有效的疾病修饰治疗方法，但目前仍不可用。越来越多的证据表明，胃肠道失调和微生物失调可能通过充当原发性或继发性病理生理因素在神经退行性变中发挥重要作用。关于微生物群在神经退行性变中的作用的研究仍处于早期阶段；然而，越来越多的证据表明，微生物失调可能通过破坏线粒体功能和诱导与线粒体功能障碍相关的衰老（MiDAS）来促进神经退行性疾病，这可能是由于基于线粒体和细菌共同进化起源的双向串扰。细胞衰老（cellular senescence）是一种抗肿瘤的稳态机制，在暴露于有害刺激时导致不可逆的细胞周期停滞。衰老细胞通过衰老细胞抗凋亡途径（SCAPs）抵抗细胞凋亡，并转变为称为衰老相关分泌表型（SASP）的状态，产生细胞毒性促炎微环境。细胞衰老导致由微生物失调、线粒体功能障碍、炎症和氧化应激驱动的有害恶性循环，这是一种导致神经炎症和神经退行性变的病理生理正反馈回路。线粒体靶向衰老治疗（mitochondria-targeted senotherapeutics），即一组专门设计用于通过抑制 SCAPs（衰老抑制剂）或抑制 SASP（衰老模拟物）来缓解衰老的药物，可以预防和消除 MiDAS 的有害影响。
