Department of Neurosurgery, Jinshan Hospital, Fudan University, Shanghai, 201508, China.
Department of Critical Care Medicine, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, 200127, China.
Neurochem Res. 2022 Oct;47(10):3192-3201. doi: 10.1007/s11064-022-03673-2. Epub 2022 Jul 27.
Parkinson's disease (PD) is a common neurodegenerative disease. Previously we identified tetranectin (TN) as a differentially expressed protein in the cerebrospinal fluid of PD patients, and we were surprised to find that TN knockout mice developed PD features. However, the specific role of TN in PD has not been clarified. In this study, we aimed to determine the effect of exogenous TN on cellular PD models and elucidate the underlying mechanisms. We found that exogenous TN could alleviate pre-formed-fibrils (PFFs)-induced synucleinopathies in SH-SY5Y cells and reduce the cell-to-cell transmission of α-synuclein (SYN). We also found that TN can promote the degradation of SYN by plasmin, which may account for its effect on cellular PD models. Moreover, administration of SYN/PFFs decreased the expression of TN and increased the expression of plasminogen activator inhibitor-1 (PAI-1) in SH-SY5Y cells, thereby reducing plasmin activity. Our findings depict a possible SYN-TN-plasmin interaction in which elevated levels of extracellular SYN monomers and aggregates in PD diminish the production of TN and PAI-1. Such changes lead to a reduced plasmin activity, which in turn reduces the degradation of extracellular SYN, thus forming a vicious cycle.
帕金森病（PD）是一种常见的神经退行性疾病。我们之前发现四旋蛋白（TN）是帕金森病患者脑脊液中差异表达的蛋白质，令我们惊讶的是，TN 敲除小鼠出现了帕金森病的特征。然而，TN 在 PD 中的具体作用尚未阐明。在这项研究中，我们旨在确定外源性 TN 对细胞 PD 模型的影响，并阐明其潜在机制。我们发现外源性 TN 可以减轻预形成纤维（PFFs）诱导的突触核蛋白病，并减少α-突触核蛋白（SYN）的细胞间传递。我们还发现 TN 可以促进纤溶酶对 SYN 的降解，这可能是其对细胞 PD 模型作用的机制。此外，SYN/PFFs 的给药降低了 SH-SY5Y 细胞中 TN 的表达并增加了纤溶酶原激活物抑制剂-1（PAI-1）的表达，从而降低了纤溶酶活性。我们的研究结果描绘了一个可能的 SYN-TN-纤溶酶相互作用，其中 PD 中外周 SYN 单体和聚集体的水平升高会减少 TN 和 PAI-1 的产生。这种变化导致纤溶酶活性降低，从而降低了细胞外 SYN 的降解，从而形成恶性循环。
