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RIPK1和肌萎缩侧索硬化症研究进展
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Abstract:
肌萎缩侧索硬化症(Amyotrophic lateral sclerosis, ALS)是一种慢性进展的致死性疾病，受体相互作用蛋白激酶1 (Receptor-interacting protein kinase 1, RIPK1)可能是治疗ALS的关键靶点。在RIPK1介导的程序性坏死中，RIPK1的激活主要受其泛素化和磷酸化调节，其中K63泛素化和M1泛素化及其下游的磷酸化决定是否激活RIPK1以介导细胞生存或死亡。在RIPK1介导的炎症中，RIPK1通过介导炎症基因的表达或者炎症因子的转录直接促进炎症的发生，或者通过调控小胶质细胞来介导脊髓炎症微环境。因此，RIPK1可能是ALS发病关键因素。目前已有用于治疗ALS的RIPK1抑制剂进入临床试验，但是其在炎症性疾病的进一步研究中发现疗效欠佳。最近研究发现在SOD1G93A小鼠中遗传失活RIPK1并不会改善其病理和临床表现，这为以RIPK1为靶点治疗ALS提供了不同的见解。
Amyotrophic lateral sclerosis (ALS) is a chronic progressive fatal disease, and receptor-interacting protein kinase 1 (RIPK1) may be a key target for the treatment of ALS. In RIPK1-mediated pro-grammed necrosis, the activation of RIPK1 is mainly regulated by its ubiquitination and phos-phorylation. K63 ubiquitination and M1 ubiquitination and their downstream phosphorylation determine whether RIPK1 is activated to mediate cell survival or death. In RIPK1-mediated in-flammation, RIPK1 directly promotes the occurrence of inflammation by mediating the expression of inflammatory genes or the transcription of inflammatory factors, or mediates the spinal cord inflammatory microenvironment by regulating microglia. Therefore, RIPK1 is a key factor in the pathogenesis of ALS. At present, RIPK1 inhibitor used to treat ALS has entered clinical trials, but it was found to be less effective in further research on inflammatory diseases. Recent studies have found that genetic inactivation of RIPK1 in SOD1G93A mice does not improve its pathological and clinical manifestations, which may be the reason for the lack of efficacy of RIPK1 inhibitors in clinical trials.
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