Kurochkina Natalya, Bhaskar Manju, Yadav Sharda Prasad, Pant Harish C
Department of Biophysics, The School of Theoretical Modeling, Washington, DC, United States.
Neuronal Cytoskeletal Protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.
Front Mol Neurosci. 2018 Oct 8;11:373. doi: 10.3389/fnmol.2018.00373. eCollection 2018.
Cellular localization, assembly and abnormal aggregation of neurofilaments depend on phosphorylation. Pathological processes associated with neurodegeneration exhibit aberrant accumulation of microtubule associated aggregated forms of hyperphosphorylated neuronal protein tau in cell bodies. These processes are critical for the disease progression in patients suffering from Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. In healthy cells, tau is localized in axons. Topographic regulation suggests that whereas the sites of synthesis of kinases and neurofilaments are the cell bodies, and sites of their functional assemblies are axons, phosphorylation/dephosphorylation are the key processes that arrange the molecules at their precise locations. Phosphorylation sites in the dynamic developmental and degenerative processes differ. Not all these processes are well understood. New advancements identify epigenetic factors involved in AD which account for the influence of age-related environment/genome interactions leading to the disease. Progress in proteomics highlights previously found major proteins and adds more to the list of those involved in AD. New key elements of specificity provide determinants of molecular recognition important for the assembly of macromolecular complexes. In this review, we discuss aberrant spatial distribution of neuronal polypeptides observed in neuropathies: aggregation, association with proteins of the neuronal cytoskeleton, and phosphorylation dependent dynamics. Particularly, we emphasize recent advancements in understanding the function and determinants of specific association of molecules involved in Alzheimer's disease with respect to the topographic regulation of phosphorylation in neuronal cytoskeleton and implications for the design of new therapies. Further, we address the role of various filament systems in maintenance of the shape, rigidity and dynamics of the cytoskeleton.
神经丝的细胞定位、组装及异常聚集均依赖于磷酸化作用。与神经退行性变相关的病理过程表现为细胞体内微管相关的过度磷酸化神经元蛋白tau聚集形式的异常积累。这些过程对于患有阿尔茨海默病、帕金森病和肌萎缩侧索硬化症的患者的疾病进展至关重要。在健康细胞中，tau定位于轴突。拓扑学调控表明，激酶和神经丝的合成位点是细胞体，而它们的功能组装位点是轴突，磷酸化/去磷酸化是将分子排列在其精确位置的关键过程。动态发育和退行性变过程中的磷酸化位点有所不同。并非所有这些过程都被完全理解。新的进展确定了参与阿尔茨海默病的表观遗传因素，这些因素解释了与年龄相关的环境/基因组相互作用对该疾病的影响。蛋白质组学的进展突出了先前发现的主要蛋白质，并增加了更多参与阿尔茨海默病的蛋白质。特异性的新关键元件为大分子复合物组装所需的分子识别提供了决定因素。在本综述中，我们讨论了在神经病变中观察到的神经元多肽的异常空间分布：聚集、与神经元细胞骨架蛋白的结合以及磷酸化依赖性动力学。特别地，我们强调了在理解阿尔茨海默病相关分子特异性结合的功能和决定因素方面的最新进展，这涉及神经元细胞骨架中磷酸化的拓扑学调控及其对新疗法设计的意义。此外，我们还探讨了各种细丝系统在维持细胞骨架形状、刚性和动力学方面的作用。
