Pike Adrianne F, Szabò Ildikò, Veerhuis Robert, Bubacco Luigi
Amsterdam UMC, Vrije Universiteit Amsterdam, Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam, the Netherlands.
Department of Biology, University of Padua, Padua, Italy.
NPJ Parkinsons Dis. 2022 Mar 24;8(1):32. doi: 10.1038/s41531-022-00293-z.
The pathology of Parkinson's disease (PD) is characterized by α-synuclein aggregation, microglia-mediated neuroinflammation, and dopaminergic neurodegeneration in the substantia nigra with collateral striatal dopamine signaling deficiency. Microglial NLRP3 inflammasome activation has been linked independently to each of these facets of PD pathology. The voltage-gated potassium channel Kv1.3, upregulated in microglia by α-synuclein and facilitating potassium efflux, has also been identified as a modulator of neuroinflammation and neurodegeneration in models of PD. Evidence increasingly suggests that microglial Kv1.3 is mechanistically coupled with NLRP3 inflammasome activation, which is contingent on potassium efflux. Potassium conductance also influences dopamine release from midbrain dopaminergic neurons. Dopamine, in turn, has been shown to inhibit NLRP3 inflammasome activation in microglia. In this review, we provide a literature framework for a hypothesis in which Kv1.3 activity-induced NLRP3 inflammasome activation, evoked by stimuli such as α-synuclein, could lead to microglia utilizing dopamine from adjacent dopaminergic neurons to counteract this process and fend off an activated state. If this is the case, a sufficient dopamine supply would ensure that microglia remain under control, but as dopamine is gradually siphoned from the neurons by microglial demand, NLRP3 inflammasome activation and Kv1.3 activity would progressively intensify to promote each of the three major facets of PD pathology: α-synuclein aggregation, microglia-mediated neuroinflammation, and dopaminergic neurodegeneration. Risk factors overlapping to varying degrees to render brain regions susceptible to such a mechanism would include a high density of microglia, an initially sufficient supply of dopamine, and poor insulation of the dopaminergic neurons by myelin.
帕金森病（PD）的病理学特征为α-突触核蛋白聚集、小胶质细胞介导的神经炎症以及黑质中的多巴胺能神经变性，并伴有纹状体多巴胺信号传导缺陷。小胶质细胞NLRP3炎性小体激活已被独立地与PD病理学的这些方面联系起来。电压门控钾通道Kv1.3在小胶质细胞中被α-突触核蛋白上调并促进钾外流，在PD模型中也被确定为神经炎症和神经变性的调节因子。越来越多的证据表明，小胶质细胞Kv1.3在机制上与NLRP3炎性小体激活相关联，而NLRP3炎性小体激活取决于钾外流。钾电导也影响中脑多巴胺能神经元的多巴胺释放。反过来，多巴胺已被证明可抑制小胶质细胞中NLRP3炎性小体的激活。在这篇综述中，我们提供了一个文献框架，用于阐述一个假说，即由α-突触核蛋白等刺激引发的Kv1.3活性诱导的NLRP3炎性小体激活，可能导致小胶质细胞利用来自相邻多巴胺能神经元的多巴胺来抵消这一过程并抵御激活状态。如果是这样的话，充足的多巴胺供应将确保小胶质细胞保持受控状态，但随着多巴胺因小胶质细胞的需求而逐渐从神经元中被虹吸，NLRP3炎性小体激活和Kv1.3活性将逐渐增强，以促进PD病理学的三个主要方面：α-突触核蛋白聚集、小胶质细胞介导的神经炎症和多巴胺能神经变性。在不同程度上重叠以使脑区易受这种机制影响的风险因素包括小胶质细胞的高密度、最初充足的多巴胺供应以及髓鞘对多巴胺能神经元的绝缘不良。
