Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease.
Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease.
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DOI：
10.1016/j.bmc.2013.12.046
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发表时间：
2014-09-15
影响因子：
3.5
通讯作者：
Ballatore C
中科院分区：
文献类型：
--
作者：
Brunden KR;Trojanowski JQ;Smith AB 3rd;Lee VM;Ballatore C
微管（MT）1，在所有哺乳动物细胞中发现的细胞骨架元件，在细胞结构和细胞分裂中发挥重要作用。它们在有丝分裂后中枢神经系统神经元的正常功能中特别关键，其中MT充当轴突投射中关键细胞成分在其上被运输的结构。MT通过MT相关蛋白tau稳定在轴突中，并且在几种神经退行性疾病中，包括阿尔茨海默病、额颞叶变性和帕金森病，由于蛋白从MT解离并沉积到称为神经元缠结的不溶性内含物中，tau功能似乎受到损害。tau功能的这种丧失被认为导致MT结构和功能的改变，导致可能有助于神经退行性过程的异常轴突运输。在其他神经退行性疾病中也有轴突运输缺陷的证据，包括肌萎缩性侧索硬化症和亨廷顿病，这可能至少部分是由MT改变引起的。因此，用于这种神经变性病症的可能的治疗策略是用MT稳定剂治疗，例如已经用于治疗癌症的那些。在这里，我们审查的证据轴突运输和MT的缺陷，在一些神经退行性疾病，并总结了各类已知的MT稳定剂。最后，我们强调了越来越多的证据表明，小分子MT稳定剂在神经退行性疾病的动物模型中提供了益处，并讨论了这些分子用于治疗这些中枢神经系统疾病的所需特征。
Microtubules (MTs)1, 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.
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