ACS Chem Neurosci. 2020 May 6;11(9):1218-1230. doi: 10.1021/acschemneuro.0c00096. Epub 2020 Apr 29.
Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine (ser)/threonine (Thr) kinase that has been demonstrated to be one of the most functionally diverse kinases within neurons. Cdk5 is regulated via binding with its neuron-specific regulatory subunits, p35 or p39. Cdk5-p35 activity is critical for a variety of developmental and cellular processes in the brain, including neuron migration, memory formation, microtubule regulation, and cell cycle suppression. Aberrant activation of Cdk5 via the truncated p35 byproduct, p25, is implicated in the pathogenesis of several neurodegenerative diseases. The present review highlights the importance of Cdk5 activity and function in the brain and demonstrates how deregulation of Cdk5 can contribute to the development of neurodegenerative conditions such as Alzheimer's and Parkinson's disease. Additionally, we cover past drug discovery attempts at inhibiting Cdk5-p25 activity and discuss which types of targeting strategies may prove to be the most successful moving forward.
周期蛋白依赖性激酶 5（Cdk5）是一种脯氨酸导向的丝氨酸（ser）/苏氨酸（Thr）激酶，已被证明是神经元中功能最多样化的激酶之一。Cdk5 通过与其神经元特异性调节亚基 p35 或 p39 结合来调节。Cdk5-p35 的活性对于大脑中的多种发育和细胞过程至关重要，包括神经元迁移、记忆形成、微管调节和细胞周期抑制。通过截断的 p35 副产物 p25 异常激活 Cdk5 与几种神经退行性疾病的发病机制有关。本综述强调了 Cdk5 在大脑中的活性和功能的重要性，并展示了 Cdk5 的失调如何导致阿尔茨海默病和帕金森病等神经退行性疾病的发展。此外，我们还介绍了过去抑制 Cdk5-p25 活性的药物发现尝试，并讨论了哪些类型的靶向策略可能在未来取得最成功。
