Facultat de Medicina i Ciències de la Salut, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas-CIBERNED, Universitat Rovira i Virgili, 43201 Reus, Tarragona, Spain.
Neurotox Res. 2012 Oct;22(3):195-207. doi: 10.1007/s12640-011-9277-4. Epub 2011 Oct 1.
Currently, there is no effective treatment for neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Thus, a major focus of neuroscience research is to examine the mechanisms involved in neuronal loss in order to identify potential drug targets. Recent results indicate that DNA damage and re-entry into the cell cycle may constitute a common pathway in apoptosis in neurological diseases. The role of the cell cycle in such disorders is supported by data on the brain of patients who showed an increase in cell-cycle protein expression. Indeed, studies performed in neuronal cell preparations indicate that oxidative stress could be the main mechanism responsible for cell cycle re-entry. DNA damage and repair after oxidative stress may activate the enzyme ataxia telangiectasia mutated, which is a cell-cycle regulator. Once the cell cycle is activated, the increase in the expression of transcription factor E2F-1 could induce neuronal apoptosis. Furthermore, the potential routes involved in E2F-1 induced apoptosis could be p53-dependent or p53-independent. Under this E2F-1 hypothesis of cell death, multiple mitochondria-dependent pathways may be activated, including caspase and caspase-independent signaling cascades. Finally, given that cyclin-dependent kinase inhibitory drugs have neuroprotective and anti-apoptotic effects in experimental models, their potential application for the treatment of neurological disorders should be taken into account.
目前，对于阿尔茨海默病和帕金森病等神经退行性疾病还没有有效的治疗方法。因此，神经科学研究的一个主要重点是研究神经元丧失所涉及的机制，以便确定潜在的药物靶点。最近的研究结果表明，DNA 损伤和重新进入细胞周期可能是神经疾病细胞凋亡中的一个共同途径。细胞周期在这些疾病中的作用得到了患者大脑中细胞周期蛋白表达增加的数据的支持。事实上，在神经元细胞制剂中进行的研究表明，氧化应激可能是导致细胞周期重新进入的主要机制。氧化应激后的 DNA 损伤和修复可能会激活细胞周期调节酶共济失调毛细血管扩张突变。一旦细胞周期被激活，转录因子 E2F-1 的表达增加可能会诱导神经元凋亡。此外，E2F-1 诱导的凋亡可能涉及依赖 p53 或不依赖 p53 的途径。在这种细胞死亡的 E2F-1 假设下，可能会激活多种线粒体依赖性途径，包括半胱氨酸蛋白酶和半胱氨酸蛋白酶非依赖性信号级联。最后，鉴于细胞周期蛋白依赖性激酶抑制剂在实验模型中具有神经保护和抗细胞凋亡作用，应考虑将其潜在应用于治疗神经退行性疾病。
