The Regulation Of Neuroinflammation By Omi, A Parkinson’s Disease Related Protein

Neurodegenerative diseases are chronic disorders caused by the progressive deterioration of certain neurons, including loss of sensation, motor control, and memory as well as cognitive impairment. These diseases mainly includes:Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD). Despite the phenotypic diversity of neurodegenerative disorders, insights gained in the last decade into their pathophysiology, especially through genetics, have begun to reveal some underlying themes. These include disturbances in cellular quality control mechanisms, oxidative stress, neuroinflammation, and impaired subcellular trafficking.Neuroinflammation is physiological responses which is mainly induced by microglia over-activation. Microglia, a type of glial cell, are macrophages that are resident in the brain and spinal cord. Under physiological conditions, microglia exhibit a deactivated phenotype that is associated with the production of anti-inflammatory and neurotrophic factors Microglia switch to an activated phenotype in response to pathogen invasion or tissue damage and thereby promote an inflammatory response that serves to further engage the immune system and initiate tissue repair. In most cases, this response is self-limiting, resolving once infection has been eradicated or the tissue damage has been repaired. But in some cases, Sustained inflammation is induced by persistent stimulus which is included environmental factors and the formation of endogenous factors. Although some inflammatory stimuli induce beneficial effects, uncontrolled inflammation may result in production of neurotoxic factors.Omi, also known as HtrA2, is a serine protease that was mainly localized in the mitochondria. It was originally regarded as a proapoptotic protein. Upon initiation of apoptosis, mature HtrA2is released into the cytosol, where it exacerbates apoptosis by binding to and cleaveaing the inhibitor of apoptosis proteins (IAPs). But recently, A growing body of evidence suggests that Omi is closely related to neurodegenerative diseases, Missense mutations that cause an impairment of the protease activity of Omi are associated with PD in humans and neurodegeneration in mnd2(motor neuron degeneration2) mice. Omi-knockout mice have an extremely similar phenotype to that of mnd2mice. Although many substrates of Omi have been identified those directly associated with neurodegeneration are unknown. Our study showed that Omi suppressed the activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase1and2(ERK1/2) by cleaving the upstream kinase MEK1(mitogen-activated or extracellular signal-regulated protein kinase kinase1). Knockdown of Omi in microglial cell lines led to activation of ERK1/2and resulted in degradation of IkBa [a inhibitor of nuclear factor κB (NF-κB)], resulting in NF-κB activation and the expression of genes encoding inflammatory molecules. 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 the cell line had no effect on MEK1cleavage. In the brains of mnd2mice, 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.