Abstract
Neurons are particularly susceptible to microtubule (MT) defects and deregulation of the MT cytoskeleton is considered to be a common insult during the pathogenesis of neurodegenerative disorders. Evidence that dysfunctions in the MT system have a direct role in neurodegeneration comes from findings that several forms of neurodegenerative diseases are associated with changes in genes encoding tubulins, the structural units of MTs, MT-associated proteins (MAPs), or additional factors such as MT modifying enzymes which modulating tubulin post-translational modifications (PTMs) regulate MT functions and dynamics. Efforts to use MT-targeting therapeutic agents for the treatment of neurodegenerative diseases are underway. Many of these agents have provided several benefits when tested on both in vitro and in vivo neurodegenerative model systems. Currently, the most frequently addressed therapeutic interventions include drugs that modulate MT stability or that target tubulin PTMs, such as tubulin acetylation. The purpose of this review is to provide an update on the relevance of MT dysfunctions to the process of neurodegeneration and briefly discuss advances in the use of MT-targeting drugs for the treatment of neurodegenerative disorders.
Highlights
Microtubules (MTs) are structurally and functionally important components of the cell cytoskeleton, providing most of the spatial organization in the cell, and regulating different cellular functions such as intracellular trafficking, cell division, and organelle positioning.They are characterized by a great chemical and functional heterogeneity, and are subjected to highly dynamic regulatory mechanisms that modulate MT composition, tubulin chemical modification, and MT association with other proteins
Specific mutations in tubulin genes, dysfunctions of MT-associated proteins (MAPs), and alterations in the levels of tubulin post-translational modifications (PTMs) are associated with different forms of neurodegenerative diseases
MT-oriented approaches currently represent one of the most promising strategies in the field of neurodegenerative diseases as several works have demonstrated that these compounds are effectively able to prevent or partially rescue MT dysfunctions in different animal and cellular models and that some of them have been translated into clinical trials
Summary
Microtubules (MTs) are structurally and functionally important components of the cell cytoskeleton, providing most of the spatial organization in the cell, and regulating different cellular functions such as intracellular trafficking, cell division, and organelle positioning They are characterized by a great chemical and functional heterogeneity, and are subjected to highly dynamic regulatory mechanisms that modulate MT composition, tubulin chemical modification, and MT association with other proteins. Specific mutations in tubulin genes, dysfunctions of MT-associated proteins (MAPs), and alterations in the levels of tubulin PTMs are associated with different forms of neurodegenerative diseases This discovery has recently allowed the development of compounds aimed to counteract neurodegeneration by restoring the correct functioning of MTs. recently, MT-oriented approaches currently represent one of the most promising strategies in the field of neurodegenerative diseases as several works have demonstrated that these compounds are effectively able to prevent or partially rescue MT dysfunctions in different animal and cellular models and that some of them have been translated into clinical trials. These results lead us to believe that in the near future, more preclinical approaches will be translated to patients, improving survival and their quality of life
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