Brunden Kurt R, Trojanowski John Q, Smith Amos B, Lee Virginia M-Y, Ballatore Carlo
Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Maloney 3, Philadelphia, PA 19104-6323, USA.
Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Maloney 3, Philadelphia, PA 19104-6323, USA.
Bioorg Med Chem. 2014 Sep 15;22(18):5040-9. doi: 10.1016/j.bmc.2013.12.046. Epub 2013 Dec 30.
Microtubules (MTs), cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington's disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders.
微管（MTs）是存在于所有哺乳动物细胞中的细胞骨架成分，在细胞结构和细胞分裂中发挥着重要作用。它们在有丝分裂后中枢神经系统神经元的正常功能中尤为关键，在这些神经元中，微管作为关键细胞成分在轴突投射中运输的结构。微管在轴突中通过微管相关蛋白tau得以稳定，在包括阿尔茨海默病、额颞叶痴呆和帕金森病在内的几种神经退行性疾病中，由于该蛋白与微管分离并沉积为称为神经原纤维缠结的不溶性包涵体，tau的功能似乎受到损害。tau功能的丧失被认为会导致微管结构和功能的改变，从而导致异常的轴突运输，这可能促成神经退行性过程。在其他神经退行性疾病，包括肌萎缩侧索硬化症和亨廷顿舞蹈病中，也有轴突运输缺陷的证据，这可能至少部分是由微管改变导致的。因此，针对此类神经退行性疾病的一种可能治疗策略是使用微管稳定剂进行治疗，例如那些已用于癌症治疗的药物。在此，我们综述了多种神经退行性疾病中轴突运输和微管缺陷的证据，并总结了各类已知的微管稳定剂。最后，我们强调越来越多的证据表明小分子微管稳定剂在神经退行性疾病动物模型中具有益处，并讨论此类分子用于治疗这些中枢神经系统疾病所需的特性。
