Mushtaq Gohar, Greig Nigel H, Anwar Firoz, Al-Abbasi Fahad A, Zamzami Mazin A, Al-Talhi Hasan A, Kamal Mohammad A
Department of Biochemistry, College of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National, Institute on Aging, National Institutes of Health, Biomedical Research Center, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
Curr Pharm Des. 2016;22(5):527-34. doi: 10.2174/1381612822666151124235028.
Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase belonging to the family of cyclin-dependent kinases. In addition to maintaining the neuronal architecture, CDK5 plays an important role in the regulation of synaptic plasticity, neurotransmitter release, neuron migration and neurite outgrowth. Although various reports have shown links between neurodegeneration and deregulation of cyclin-dependent kinases, the specific role of CDK5 inhibition in causing neuroprotection in cases of neuronal insult or in neurodegenerative diseases is not wellunderstood. This article discusses current evidence for the involvement of CDK5 deregulation in neurodegenerative disorders and neurodegeneration associated with stroke through various mechanisms. These include upregulation of cyclin D1 and overactivation of CDK5 mediated neuronal cell death pathways, aberrant hyperphosphorylation of human tau proteins and/or neurofilament proteins, formation of neurofibrillary lesions, excitotoxicity, cytoskeletal disruption, motor neuron death (due to abnormally high levels of CDK5/p25) and colchicine- induced apoptosis in cerebellar granule neurons. A better understanding of the role of CDK5 inhibition in neuroprotective mechanisms will help scientists and researchers to develop selective, safe and efficacious pharmacological inhibitors of CDK5 for therapeutic use against human neurodegenerative disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis and neuronal loss associated with stroke.
细胞周期蛋白依赖性激酶5（CDK5）是一种脯氨酸导向的丝氨酸/苏氨酸激酶，属于细胞周期蛋白依赖性激酶家族。除了维持神经元结构外，CDK5在调节突触可塑性、神经递质释放、神经元迁移和神经突生长中也起着重要作用。尽管各种报告显示神经退行性变与细胞周期蛋白依赖性激酶失调之间存在联系，但CDK5抑制在神经元损伤或神经退行性疾病中发挥神经保护作用的具体机制尚不清楚。本文通过各种机制探讨了CDK5失调参与神经退行性疾病和与中风相关的神经退行性变的现有证据。这些机制包括细胞周期蛋白D1上调和CDK5介导的神经元细胞死亡途径过度激活、人tau蛋白和/或神经丝蛋白异常过度磷酸化、神经原纤维病变形成、兴奋性毒性、细胞骨架破坏、运动神经元死亡（由于CDK5/p25水平异常升高）以及秋水仙碱诱导的小脑颗粒神经元凋亡。更好地理解CDK5抑制在神经保护机制中的作用将有助于科学家和研究人员开发选择性、安全且有效的CDK5药理学抑制剂，用于治疗人类神经退行性疾病，如阿尔茨海默病、肌萎缩侧索硬化症以及与中风相关的神经元损失。
