Department of Biomedical and Biotechnological Sciences (BIOMETEC), Pharmacology Section, Medical School, University of Catania, Via S. Sofia 65, 95125, Catania, Italy; Oasi Research Institute-IRCCS, Neuropharmacology Section, Via Conte Ruggero 73, 94018, Troina, EN, Italy.
Redox Biol. 2020 Sep;36:101664. doi: 10.1016/j.redox.2020.101664. Epub 2020 Aug 1.
Oxidative stress and inflammation have long been recognized to contribute to Parkinson's disease (PD), a common movement disorder characterized by the selective loss of midbrain dopaminergic neurons (mDAn) of the substantia nigra pars compacta (SNpc). The causes and mechanisms still remain elusive, but a complex interplay between several genes and a number of interconnected environmental factors, are chiefly involved in mDAn demise, as they intersect the key cellular functions affected in PD, such as the inflammatory response, mitochondrial, lysosomal, proteosomal and autophagic functions. Nuclear factor erythroid 2 -like 2 (NFE2L2/Nrf2), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless (Wnt)/β-catenin signaling cascade, a vital pathway for mDAn neurogenesis and neuroprotection, emerge as critical intertwinned actors in mDAn physiopathology, as a decline of an Nrf2/Wnt/β-catenin prosurvival axis with age underlying PD mutations and a variety of noxious environmental exposures drive PD neurodegeneration. Unexpectedly, astrocytes, the so-called "star-shaped" cells, harbouring an arsenal of "beneficial" and "harmful" molecules represent the turning point in the physiopathological and therapeutical scenario of PD. Fascinatingly, "astrocyte's fil rouge" brings back to Nrf2/Wnt resilience, as boosting the Nrf2/Wnt resilience program rejuvenates astrocytes, in turn (i) mitigating nigrostriatal degeneration of aged mice, (ii) reactivating neural stem progenitor cell proliferation and neuron differentiation in the brain and (iii) promoting a beneficial immunomodulation via bidirectional communication with mDAns. Then, through resilience of Nrf2/Wnt/β-catenin anti-ageing, prosurvival and proregenerative molecular programs, it seems possible to boost the inherent endogenous self-repair mechanisms. Here, the cellular and molecular aspects as well as the therapeutical options for rejuvenating glia-neuron dialogue will be discussed together with major glial-derived mechanisms and therapies that will be fundamental to the identification of novel diagnostic tools and treatments for neurodegenerative diseases (NDs), to fight ageing and nigrostriatal DAergic degeneration and promote functional recovery.
氧化应激和炎症长期以来被认为是导致帕金森病（PD）的原因，PD 是一种常见的运动障碍，其特征是中脑黑质致密部（SNpc）的多巴胺能神经元（mDAn）选择性丧失。其病因和发病机制仍不清楚，但多个基因和许多相互关联的环境因素之间的复杂相互作用，主要涉及 mDAn 的死亡，因为它们与 PD 中受影响的关键细胞功能交叉，如炎症反应、线粒体、溶酶体、蛋白酶体和自噬功能。核因子红细胞 2 样 2（NFE2L2/Nrf2）是细胞抵御氧化应激和炎症的主要调节剂，Wingless（Wnt）/β-连环蛋白信号级联是 mDAn 神经发生和神经保护的重要途径，它们在 mDAn 病理生理学中是关键的相互交织的因素，因为随着年龄的增长，Nrf2/Wnt/β-连环蛋白的生存轴下降，PD 突变和各种有害的环境暴露驱动 PD 神经退行性变。出乎意料的是，星形胶质细胞，所谓的“星形”细胞，拥有一系列“有益”和“有害”的分子，代表着 PD 病理生理学和治疗学的转折点。有趣的是，“星形胶质细胞的红线”又回到了 Nrf2/Wnt 的恢复，因为增强 Nrf2/Wnt 的恢复程序可以使星形胶质细胞恢复活力，从而（i）减轻老年小鼠的黑质纹状体变性，（ii）在大脑中重新激活神经干细胞祖细胞的增殖和神经元分化，以及（iii）通过与 mDAn 的双向通讯促进有益的免疫调节。然后，通过 Nrf2/Wnt/β-连环蛋白抗衰老、生存和促进再生的分子程序的恢复，似乎可以增强内在的内源性自我修复机制。在这里，将讨论细胞和分子方面以及恢复神经胶质-神经元对话的治疗选择，以及主要的神经胶质衍生机制和治疗方法，这对于识别神经退行性疾病（NDs）的新型诊断工具和治疗方法、对抗衰老和黑质纹状体 DA 能变性以及促进功能恢复至关重要。
