Mitogen-Activated Protein Kinase Pathway in Amyotrophic Lateral Sclerosis.
Mitogen-Activated Protein Kinase Pathway in Amyotrophic Lateral Sclerosis.
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DOI：
10.3390/biomedicines9080969
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发表时间：
2021-08-06
期刊：
影响因子：
4.7
通讯作者：
Zhang K
中科院分区：
文献类型：
--
作者：
Sahana TG;Zhang K
肌萎缩侧索硬化症是一种致死性运动神经元退行性疾病。多种遗传和非遗传风险因素与疾病发病机制相关，并且几种细胞过程，包括蛋白质稳态、RNA代谢、囊泡运输等，在肌萎缩侧索硬化症中严重受损尽管疾病表现和进展具有异质性，但ALS患者在运动皮质和脊髓组织中显示出蛋白质聚集体，这被认为至少部分是由异常相分离和持续应激颗粒的形成引起的。与这一观点一致，许多研究表明细胞应激，如ER应激，DNA损伤，氧化应激和生长因子耗竭，在ALS条件。丝裂原活化蛋白激酶（MAPK）途径是调节细胞增殖、分化、存活和死亡的基本的丝裂原/应激活化的信号转导途径。本文就MAPK在ALS的生理学和发病机制中的重要作用作一综述。我们还讨论了在临床前模型中测试的靶向这一途径的药理学抑制剂，表明它们作为潜在候选药物的作用。
Amyotrophic lateral sclerosis is a fatal motor neuron degenerative disease. Multiple genetic and non-genetic risk factors are associated with disease pathogenesis, and several cellular processes, including protein homeostasis, RNA metabolism, vesicle transport, etc., are severely impaired in ALS conditions. Despite the heterogeneity of the disease manifestation and progression, ALS patients show protein aggregates in the motor cortex and spinal cord tissue, which is believed to be at least partially caused by aberrant phase separation and the formation of persistent stress granules. Consistent with this notion, many studies have implicated cellular stress, such as ER stress, DNA damage, oxidative stress, and growth factor depletion, in ALS conditions. The mitogen-activated protein kinase (MAPK) pathway is a fundamental mitogen/stress-activated signal transduction pathway that regulates cell proliferation, differentiation, survival, and death. Here we summarize the fundamental role of MAPK in physiology and ALS pathogenesis. We also discuss pharmacological inhibitors targeting this pathway tested in pre-clinical models, suggesting their role as potential drug candidates.
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