Reuland Carolyn J, Church Frank C
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599-7525, USA.
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599-7525, USA.
Med Hypotheses. 2020 May;138:109602. doi: 10.1016/j.mehy.2020.109602. Epub 2020 Jan 28.
Parkinson's disease (PD) is a progressive degenerative nervous system disorder and is the second most common neurodegenerative disorder in the elderly population. The disease originates from the loss of dopamine-producing neurons in the substantia nigra in the brain, resulting in unregulated activity of the basal ganglia. Αlpha-synuclein (α-syn) is a protein found to aggregate in the substantia nigra region of patients with PD, forming Lewy Body inclusions; its aggregation may contribute to neuronal cell death in PD. This work hypothesizes about the synergistic relationship between α-syn aggregation and neuroinflammation to up-regulate expression of the serine protease inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1). The protease, plasmin, has been shown to cleave extracellular α-syn (including its monomeric, oligomeric, and fibrillary forms), resulting in less aggregation and Lewy Body formation. The zymogen plasminogen is converted to its active serine protease form, plasmin, either by tissue plasminogen activator (tPA) or by urokinase plasminogen activator (uPA) bound to urokinase receptor (uPAR). Both tPA and uPA/uPAR are inhibited by PAI-1. Thus, when PAI-1 levels increase, less plasmin is generated, which would lead to reduced proteolysis of α-syn. Expression of PAI-1 is increased both in inflammatory environments and in the presence of extracellular α-syn aggregates. This scenario suggests a pathological amplification loop: increased extracellular α-syn aggregation activates an inflammatory response from microglia and astrocytes, increasing PAI-1 levels, and decreasing the generation of plasmin. With reduced plasmin, less α-syn can be cleaved, and aggregation continues, sustaining the pathological process. Understanding this putative pathogenic loop could provide insight into the means by which neurodegeneration progresses in PD, and it may offer possible novel therapeutic strategies.
帕金森病（PD）是一种进行性退行性神经系统疾病，是老年人群中第二常见的神经退行性疾病。该疾病源于大脑黑质中产生多巴胺的神经元的丧失，导致基底神经节活动失调。α-突触核蛋白（α-syn）是一种在帕金森病患者黑质区域聚集的蛋白质，形成路易小体包涵体；其聚集可能导致帕金森病中的神经元细胞死亡。这项研究假设α-突触核蛋白聚集与神经炎症之间存在协同关系，以上调丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）纤溶酶原激活物抑制剂-1（PAI-1）的表达。蛋白酶纤溶酶已被证明可切割细胞外α-突触核蛋白（包括其单体、寡聚体和纤维状形式），从而减少聚集和路易小体的形成。酶原纤溶酶原通过组织纤溶酶原激活物（tPA）或与尿激酶受体（uPAR）结合的尿激酶纤溶酶原激活物（uPA）转化为其活性丝氨酸蛋白酶形式纤溶酶。tPA和uPA/uPAR均被PAI-1抑制。因此，当PAI-1水平升高时，产生的纤溶酶减少，这将导致α-突触核蛋白的蛋白水解减少。PAI-1的表达在炎症环境和细胞外α-突触核蛋白聚集体存在时均会增加。这种情况表明存在一个病理放大循环：细胞外α-突触核蛋白聚集增加会激活小胶质细胞和星形胶质细胞的炎症反应，增加PAI-1水平，并减少纤溶酶的产生。随着纤溶酶减少，可被切割的α-突触核蛋白减少，聚集持续，维持病理过程。了解这个假定的致病循环可以深入了解帕金森病中神经退行性变的进展方式，并且可能提供新的治疗策略。
