Microtubule-modulating Agents in the Fight Against Neurodegeneration: Will it ever Work?
Microtubule-modulating Agents in the Fight Against Neurodegeneration: Will it ever Work?
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DOI：
10.2174/1570159x19666211201101020
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发表时间：
2022
影响因子：
5.3
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中科院分区：
文献类型：
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微管骨架在神经细胞中起着至关重要的作用，作为形态学最重要的结构决定因素和轴突运输过程的高速公路。许多神经退行性疾病的特征在于微管和微管调节蛋白（如微管相关蛋白tau）的结构和组织的变化，其在统称为tau蛋白病的一类疾病中表现出特征性变化。微管动力学的变化似乎发生在神经退行性疾病的早期，也可能导致与年龄相关的神经元功能障碍。因此，调节微管动力学和纠正受损的微管稳定性可以是一种有用的神经保护策略，以抵消疾病和衰老中微管系统的破坏。在这篇文章中，我们回顾了目前的微管为药物靶点的神经退行性疾病的治疗微管为导向的方法，tau蛋白为药物靶点，和翻译后修饰的微管系统的潜在修饰剂。我们讨论的方法，可以追溯到相当不具体的作用机制，这会导致不良的副作用，在非神经元细胞类型或这是由于非微管相关的相互作用的中断的限制。我们还就如何提高方法的特异性以及可以用于调节物质的进一步目标提出了一些想法。
The microtubule skeleton plays an essential role in nerve cells as the most important structural determinant of morphology and as a highway for axonal transport processes. Many neurodegenerative diseases are characterized by changes in the structure and organization of microtubules and microtubule-regulating proteins such as the microtubule-associated protein tau, which exhibits characteristic changes in a whole class of diseases collectively referred to as tauopathies. Changes in the dynamics of microtubules appear to occur early under neurodegenerative conditions and are also likely to contribute to age-related dysfunction of neurons. Thus, modulating microtubule dynamics and correcting impaired microtubule stability can be a useful neuroprotective strategy to counteract the disruption of the microtubule system in disease and aging. In this article, we review current microtubule-directed approaches for the treatment of neurodegenerative diseases with microtubules as a drug target, tau as a drug target, and post-translational modifications as potential modifiers of the microtubule system. We discuss limitations of the approaches that can be traced back to the rather unspecific mechanism of action, which causes undesirable side effects in non-neuronal cell types or which are due to the disruption of non-microtubule-related interactions. We also develop some thoughts on how the specificity of the approaches can be improved and what further targets could be used for modulating substances.