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

Abstract

: 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 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 drug target, tau as drug target, and posttranslational 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 on 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.

Multiple pathways promote microtubule stabilization in senescent intestinal epithelial cells

“…Thus, we identified a previously unknown mechanism that promotes epithelial cell senescence through microtubule stabilization. This information is especially relevant in the context of therapeutic treatments that employ modulators of microtubule stability, such as therapies for neurodegeneration or cancer 54 , 55 .…”

Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule regulation

“…Therefore, drugs that inhibit tau aggregation or increase the interaction of tau with microtubules could be a promising approach to combat tau-induced neurodegeneration. In fact, several drug candidates aiming to inhibit tau aggregation, reduce tau phosphorylation, or decrease tau expression are under investigation (Soliman et al, 2022). However, mechanism-based drug assays are difficult to establish due to the lack of cell-based models that allow to monitor tau aggregation and effects on tau-microtubule interaction of the full-length tau protein.…”

“…Due to the failure of A β -targeted therapies, tau has become a target of rapidly evolving therapeutic strategies (Chang et al, 2021; Soliman et al, 2022). However, tau is a challenging target due to its complex interactions as an intrinsically disordered protein, its various post-translational modifications, and the complexity of tau pathologies (Brandt et al, 2020; Limorenko and Lashuel, 2021; Shi et al, 2021).…”

Super-resolution imaging and quantitative analysis of microtubule arrays in model neurons show that epothilone D increases the density but decreases the length and straightness of microtubules in axon-like processes

“…In addition, sensitive methods to analyze changes in the neuronal microtubule array would be of great use for the identification and characterization of potential drugs that interfere with microtubule structure and dynamics. Such microtubule-targeting agents (MTAs), which include the epothilones that have been shown to cross the blood-brain barrier and have the potential to modulate neuronal microtubule dynamics and stability, may have the potential to restore disrupted microtubule-dependent processes during neurodegeneration ( Ruschel et al, 2015 , Soliman et al, 2022 ). However, the small diameter of neuronal processes and the densely packed microtubule organization make the visualization and quantitative assessment of changes in microtubule organization very challenging.…”