Microtubule-modulating Agents in the Fight Against Neurodegeneration: Will it ever Work?

: The microtubule skeleton plays an essential role in nerve cells as the most importantstructural determinant of morphology and as a highway for axonal transport processes. Many neurodegenerativediseases are characterized by changes in the structure and organization of microtubulesand microtubule-regulating proteins such as the microtubule-associated protein tau, which exhibitscharacteristic changes in a whole class of diseases collectively referred to as tauopathies. Changes inthe dynamics of microtubules appear to occur early under neurodegenerative conditions and are alsolikely to contribute to age-related dysfunction of neurons. Thus, modulating microtubule dynamicsand correcting impaired microtubule stability can be a useful neuroprotective strategy to counteractthe 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 asa drug target, tau as a drug target, and post-translational modifications as potential modifiers of themicrotubule system. We discuss limitations of the approaches that can be traced back to the ratherunspecific mechanism of action, which causes undesirable side effects in non-neuronal cell types orwhich are due to the disruption of non-microtubule-related interactions. We also develop somethoughts on how the specificity of the approaches can be improved and what further targets could beused for modulating substances.