Microtubules in Neurons
Microtubule Basics
Microtubules are hollow polymers of tubulin subunits. The binding of a-and b-tubulin dimers form a hollow tube with an outer diameter of 25 nm. Although both microtubule ends can grow and depolymerize, the dynamics of the two microtubule ends are very different. The minus ends that are slow-growing are usually anchored to the centrosome, responsible for nucleating microtubules, whereas plus-ends that are fast-growing grow outwards towards the cell periphery. The assembly of microtubule-based structures depends on many microtubule-related proteins, such as plus-end tracking proteins (+TIPs) and some coordinated actions of many additional regulatory factors, such as neuron-specific tubulin isotypes post-translational modifications (PTMs) and motor proteins.
Microtubule Organization in Neurons
Neurons are exquisitely polarized cells whose morphology, structure, and function depend on the microtubules. Microtubules sculpt neuronal structure and mediate the transport of RNAs, proteins, vesicles, and organelles that sustain neuronal activity. Because of their organization and function and microtubule-associated proteins, microtubules in dendrites differ from those in axons. These differences could be coupled with microtubule post-translational modifications to combine the regulation of intracellular transport, morphology, and function locally.
Fig.1 Microtubule organization in the vertebrate neuron. (Baas, 2016)
Features of Microtubule in Neurons
- Polarity
- Stability
In mature neurons, the microtubule is intrinsically polar. The end exposing-tubulin subunits are the so-called minus-end, whereas-tubulin subunits are exposed at the plus-end. The polarity of microtubules is crucial to their function, and the polarity orientation in different neurons is a significant determinant of where particular cargoes are transported.
Some free tubulin subunits and other stable microtubules in the neurons always dynamically exchange such that microtubules undergo bouts of assembly and disassembly. In increasing and developing cells, most microtubules are very dynamic. Many microtubules are stabilized in differentiated neurons. Recent work demonstrates that the stability of microtubules is crucial to the development of the nervous system to determine axon formation and maintain the identity of axons, and they regulate the dynamics of dendritic spines.
Fig.2 Stability domains of axonal microtubules and related molecules and modifications. (Baas, 2016)
Roles of Microtubules
- As architectural elements
- As railways for molecular proteins convey cargo
The microtubule cytoskeleton is a central architectural element in the neuron for the morphogenesis and maintenance of neurons. Microtubules arranged with distinct polarities in axons and dendrites and provide a structural backbone for axons and dendrites to maintain their specialized morphologies. Microtubules are regarded as critical structures for stable neuronal morphology because of their dynamic and mechanical functions.
Microtubules are significant tracks for long-distance transport. In the microtubules of axons and dendrites, proteins and organelles can be actively transported in both directions. Neuronal microtubules guide intracellular transport and induce morphological changes during the various phases of neuronal development and synapse formation.
Fig.3 Microtubules carry out diverse roles within neurons. (Kelliher, 2019)
Microtubule Stability in Nervous System Diseases
Deficiencies in microtubule-related genes cause many neurodevelopmental problems and neurodegenerative disorders. Recently, microtubule-stabilizing drugs have been shown to impact the regenerative capacity of injured adult CNS axons positively. Advances in discovering microtubule-targeting agents (MTAs) and synthesizing small molecules that modulate microtubule-based processes might offer new therapeutic paradigms to treat neurological defects and intervene in neurodegenerative processes. Although these MTAs are potentially helpful in treating nerve injury and neurodegenerative diseases, they are now primarily used for anticancer therapies and have been shown to cause unwanted side effects in the rest of the body. Therefore, future therapeutic strategies may focus on interventions at the level of microtubule-associated proteins or related signaling pathways. Further advances in understanding the function of microtubule-related proteins and the regulatory mechanism of microtubules in both scar-forming fibroblasts and axons may lead to improved targeting and development of therapeutics for neurodegenerative diseases.
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References
- Baas, P. W.; et al. Stability properties of neuronal microtubules. Cytoskeleton. 2016, 73(9), 442-460.
- Kelliher, M. T.; et al. Microtubule control of functional architecture in neurons. Current opinion in neurobiology. 2019, 57, 39-45.
