Laboratory of Molecular Neuropathology, Key Laboratory of Brain Function and Diseases and School of Life Sciences, University of Science and Technology of China, Chinese Academy of Sciences, Hefei, Anhui 230027, China.
Sci Signal. 2012 Aug 21;5(238):ra61. doi: 10.1126/scisignal.2002946.
Inflammation in Parkinson's disease is closely associated with disease pathogenesis. Mutations in Omi, which encodes the protease Omi, are linked to neurodegeneration and Parkinson's disease in humans and in mouse models. The severe neurodegeneration and neuroinflammation that occur in mnd2 (motor neuron degeneration 2) mice result from loss of the protease activity of Omi by the point mutation S276C; however, the substrates of Omi that induce neurodegeneration are unknown. We showed that Omi was required for the production of inflammatory molecules by microglia, which are the resident macrophages in the central nervous system. Omi suppressed the activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 1 and 2 (ERK1/2) by cleaving the upstream kinase MEK1 (mitogen-activated or extracellular signal-regulated protein kinase kinase 1). Knockdown of Omi in microglial cell lines led to activation of ERK1/2 and resulted in degradation of IκBα [α inhibitor of nuclear factor κB (NF-κB)], resulting in NF-κB activation and the expression of genes encoding inflammatory molecules, such as tumor necrosis factor-α and inducible nitric oxide synthase. The production of inflammatory molecules induced by the knockdown of Omi was blocked by the MEK1-specific inhibitor U0126. Furthermore, expression of the protease-deficient S276C Omi mutant in a microglial cell line had no effect on MEK1 cleavage or ERK1/2 activation. In the brains of mnd2 mice, we observed increased transcription of several genes encoding inflammatory molecules, as well as activation of astrocytes and microglia. Therefore, our study demonstrates that Omi is an intrinsic cellular factor that inhibits neuroinflammation.
帕金森病中的炎症与疾病发病机制密切相关。Omi 编码蛋白酶 Omi，其突变与人类和小鼠模型中的神经退行性变和帕金森病有关。mnd2（运动神经元退行性变 2）小鼠中严重的神经退行性变和神经炎症是由 Omi 的点突变 S276C 导致其蛋白酶活性丧失引起的；然而，诱导神经退行性变的 Omi 底物尚不清楚。我们表明，Omi 是小胶质细胞（中枢神经系统中的常驻巨噬细胞）产生炎症分子所必需的。Omi 通过切割上游激酶 MEK1（丝裂原激活或细胞外信号调节蛋白激酶激酶 1）来抑制丝裂原激活蛋白激酶（MAPKs）细胞外信号调节激酶 1 和 2（ERK1/2）的激活。在小胶质细胞系中敲低 Omi 会导致 ERK1/2 的激活，并导致 IκBα[核因子κB（NF-κB）的α抑制剂]降解，从而导致 NF-κB 激活和编码炎症分子的基因表达，如肿瘤坏死因子-α和诱导型一氧化氮合酶。Omi 敲低诱导的炎症分子的产生被 MEK1 特异性抑制剂 U0126 阻断。此外，在小胶质细胞系中表达无蛋白酶活性的 S276C Omi 突变体对 MEK1 切割或 ERK1/2 激活没有影响。在 mnd2 小鼠的大脑中，我们观察到几个编码炎症分子的基因转录增加，以及星形胶质细胞和小胶质细胞的激活。因此，我们的研究表明 Omi 是一种内在的细胞因子，可抑制神经炎症。
