Laboratory of Neuronal Cytoskeletal Protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Histochem Cell Biol. 2013 Jul;140(1):23-32. doi: 10.1007/s00418-013-1108-7. Epub 2013 Jun 23.
The neuronal cytoskeleton is tightly regulated by phosphorylation and dephosphorylation reactions mediated by numerous associated kinases, phosphatases and their regulators. Defects in the relative kinase and phosphatase activities and/or deregulation of compartment-specific phosphorylation result in neurodegenerative disorders. The largest family of cytoskeletal proteins in mammalian cells is the superfamily of intermediate filaments (IFs). The neurofilament (NF) proteins are the major IFs. Aggregated forms of hyperphosphorylated tau and phosphorylated NFs are found in pathological cell body accumulations in the central nervous system of patients suffering from Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. The precise mechanisms for this compartment-specific phosphorylation of cytoskeletal proteins are not completely understood. In this review, we focus on the mechanisms of neurofilament phosphorylation in normal physiology and neurodegenerative diseases. We also address the recent breakthroughs in our understanding the role of different kinases and phosphatases involved in regulating the phosphorylation status of the NFs. In addition, special emphasis has been given to describe the role of phosphatases and Pin1 in phosphorylation of NFs.
神经元细胞骨架的磷酸化和去磷酸化反应受到许多相关激酶、磷酸酶及其调节因子的严格调控。相对激酶和磷酸酶活性的缺陷和/或特定隔室磷酸化的失调导致神经退行性疾病。在哺乳动物细胞中，细胞骨架蛋白最大的家族是中间丝（IF）超家族。神经丝（NF）蛋白是主要的 IF。在患有阿尔茨海默病、帕金森病和肌萎缩性侧索硬化症的患者的中枢神经系统中，病理性细胞体堆积中发现了过度磷酸化的 tau 和磷酸化的 NF 的聚集形式。这种细胞骨架蛋白特定隔室磷酸化的确切机制尚不完全清楚。在这篇综述中，我们重点介绍 NF 磷酸化在正常生理和神经退行性疾病中的机制。我们还讨论了我们对调节 NF 磷酸化状态的不同激酶和磷酸酶的作用的最新理解的突破。此外，特别强调了描述磷酸酶和 Pin1 在 NF 磷酸化中的作用。
