Department of Neurobiology, Osnabrück University, Osnabrück, Germany.
Center for Cellular Nanoanalytics, Osnabrück University, Osnabrück, Germany.
Curr Neuropharmacol. 2022;20(4):782-798. doi: 10.2174/1570159X19666211201101020.
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.
微管骨架作为形态的最重要结构决定因素和轴突运输过程的高速公路，在神经细胞中起着至关重要的作用。许多神经退行性疾病的特征是微管和微管调节蛋白（如微管相关蛋白 tau）的结构和组织发生变化，tau 表现出一类被统称为 tau 病的疾病的特征性变化。微管动力学的变化似乎在神经退行性条件下很早就发生了，并且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能是一种有用的神经保护策略，以对抗疾病和衰老中微管系统的破坏。在本文中，我们回顾了目前以微管为药物靶点、tau 为药物靶点以及翻译后修饰为潜在的微管系统调节剂治疗神经退行性疾病的微管定向方法。我们讨论了这些方法的局限性，这些局限性可以追溯到作用机制相当不特异，这会导致非神经元细胞类型产生不良的副作用，或者由于破坏了非微管相关的相互作用。我们还就如何提高方法的特异性以及可以使用哪些进一步的靶标来调节物质进行了一些思考。
