Institute of Cardiological Research, University of Buenos Aires, National Research Council (ININCA-UBA-CONICET), Marcelo T. de Alvear 2270, C1122 Buenos Aires, Argentina.
Pontifical Catholic University of Argentina, Buenos Aires, Argentina.
Neural Plast. 2020 Feb 7;2020:1859431. doi: 10.1155/2020/1859431. eCollection 2020.
Despite the fact that astrocytes are the most abundant glial cells, critical for brain function, few studies have dealt with their possible role in neurodegenerative diseases like Parkinson's disease (PD). This article explores relevant evidence on the involvement of astrocytes in experimental PD neurodegeneration from a molecular signaling perspective. For a long time, astrocytic proliferation was merely considered a byproduct of neuroinflammation, but by the time being, it is clear that astrocytic dysfunction plays a far more important role in PD pathophysiology. Indeed, ongoing experimental evidence suggests the importance of astrocytes and dopaminergic neurons' cross-linking signaling pathways. The Wnt-1 (wingless-type MMTV integration site family, member 1) pathway regulates several processes including neuron survival, synapse plasticity, and neurogenesis. In PD animal models, Frizzled (Fzd) neuronal receptors' activation by the Wnt-1 normally released by astrocytes following injuries leads to -catenin-dependent gene expression, favoring neuron survival and viability. The transient receptor potential vanilloid 1 (TRPV1) capsaicin receptor also participates in experimental PD genesis. Activation of astrocyte TRPV1 receptors by noxious stimuli results in reduced inflammatory response and increased ciliary neurotrophic factor (CNTF) synthesis, which enhances neuronal survival and differentiation. Another major pathway involves IB kinase (IKK) downregulation by ARL6ip5 (ADP-ribosylation-like factor 6 interacting protein 5, encoded by the cell differentiation-associated, JWA, gene). Typically, IKK releases the proinflammatory NF-B (nuclear factor kappa-light-chain-enhancer of activated B cells) molecule from its inhibitor. Therefore, by downregulating NF-B inhibitor, ARL6ip5 promotes an anti-inflammatory response. The evidence provided by neurotoxin-induced PD animal models guarantees further research on the neuroprotective potential of normalizing astrocyte function in PD.
尽管星形胶质细胞是最丰富的神经胶质细胞，对大脑功能至关重要，但很少有研究涉及它们在帕金森病 (PD) 等神经退行性疾病中的可能作用。本文从分子信号的角度探讨了星形胶质细胞在实验性 PD 神经退行性变中的相关证据。长期以来，星形胶质细胞的增殖仅仅被认为是神经炎症的副产品，但现在清楚的是，星形胶质细胞功能障碍在 PD 病理生理学中起着更为重要的作用。事实上，正在进行的实验证据表明星形胶质细胞和多巴胺能神经元交联信号通路的重要性。Wnt-1（无翅型 MMV 整合位点家族成员 1）途径调节包括神经元存活、突触可塑性和神经发生在内的几个过程。在 PD 动物模型中，星形胶质细胞正常释放的 Wnt-1 激活 Frizzled（Fzd）神经元受体后，导致-catenin 依赖性基因表达，有利于神经元存活和活力。瞬时受体电位香草酸 1（TRPV1）辣椒素受体也参与了实验性 PD 的发生。伤害性刺激激活星形胶质细胞 TRPV1 受体可减少炎症反应，增加睫状神经营养因子 (CNTF) 的合成，从而增强神经元的存活和分化。另一个主要途径涉及 ARL6ip5（ADP-ribosylation-like factor 6 interacting protein 5，由细胞分化相关的 JWA 基因编码）下调 IKK（IB 激酶）。通常，IKK 从其抑制剂中释放促炎 NF-B（核因子 kappa-轻链增强子的激活 B 细胞）分子。因此，通过下调 NF-B 抑制剂，ARL6ip5 促进抗炎反应。神经毒素诱导的 PD 动物模型提供的证据保证了进一步研究正常化星形胶质细胞功能在 PD 中的神经保护潜力。
