The world is filled with fascinating buildings, true architectural masterpieces that we admire for their grandeur, decorations, shape or simply the way they fill a space or perform a certain function. Regardless of whether we’re pondering in front of Sagrada Familia or the Taj Mahal, the London Bridge or the Tower of Pisa, there is one basic underlying principle all constructions start from: structural integrity.
Cells are similar to buildings in that way. They may come in numerous shapes and sizes, fulfill very specific and complex functions, but ultimately must contain all their composing elements into some form of strong, resilient yet dynamic structural framework. The neuron is no exception. We’ll take a look at part of that framework.
In this article, we’ll discuss:
- What is the cytoskeleton?
- What are microtubules?
- What are tubulins?
- How to ‘grow’ a microtubule
- Microtubules and memory
What is the cytoskeleton?
The cytoskeleton is, as its name suggests, the structural backbone of a cell. It is made up of long, wire-like structures that determine a cell’s length, shape and where its components are placed. There are three main structures in any cell’s cytoskeleton, which differ by length and composition: 1
Other filaments and proteins may complete the architectural framework of specific cells, but these remain the three main constants.
- Microfilaments – the thinnest of ‘wires’, made up of a protein called actin
- Intermediate filaments – as the name suggests, intermediate in thickness, made up of different proteins, depending on cell type. In neurons, these are called neurofilaments.
- Microtubules – the thickest of all, averaging about 25 nm, and made up of proteins called tubulins
What are microtubules?
Microtubules are long scaffolds that extend from one end of a neuron to the other. They provide structure and form, but this is not their only feature. For most cells, they are essential for cell division, creating the structures that ultimately pull cells apart. Some organisms even use them to move around – with microtubules being the basis for cilia and flagella.2 As neurons don’t divide or have cilia, however, this is not the microtubules’ main function in the nervous system. Instead, they play an indisputable role in transport.
These long, wire-like structures act as streets. They have two distinct ends – which we’ve come to call the minus end and the plus end - and provide support for motor proteins to move on. They are a two-way street too, in that some motor proteins may carry things from minus to plus, while others move from plus to minus.1
What would a neuron need to transport up and down in the first place, you may wonder? While it is true that much of the signal transmission in the brain is electrical in nature, we must not forget that neurons are, ultimately, biological machines. Neurotransmitters, being synthesized in the cell body and encapsulated in vesicles, need to be transported down the axon to the synapse in order to exert their effect.
Other proteins, cell components and even foreign elements travel the other way around. The tetanus toxin, for example, starts out in the periphery, at the site of an injury or bite. It travels backwards up the nerves, via the microtubules highway, to reach its final place of action: the spinal cord/brainstem. So do the herpes and polio viruses, ultimately high jacking neuronal transport mechanisms as part of their life cycles.1
What are tubulins?
Tubulins are the very building blocks of microtubules. Two main types of tubulins (alpha and beta) bind together to form a pair. Then, they link to other pairs and other pairs until they form long chains of alpha-beta-alpha-beta-alpha-beta-alpha-beta(…). These chains ultimately self-assemble to generate the full microtubules. This is a highly directed and controlled process.
First off, all this linking requires energy – which tubulins use in the form of GTP (a relative of ATP). A pair of alpha-beta tubulins has a GTP bound to them. When they decide to link with other pairs, they have to give up this GTP (as a token of energy), in order to create a strong, resilient bond.1 Sometimes, the physical properties of assembled microtubules are compared to those of the stiff plastic Plexiglas.2
However, curiously enough, tubulins can also un-link from their peers and become free again.
This variability means that, with proper control, a microtubule can become longer or shorter fairly quickly, a process called dynamic instability. That is to say, microtubules don’t have a constant length, but are able to grow or shrink permanently at the plus end, thus allowing the neuronal roadmap to re-generate and adapt itself.2
This process is highly regulated by other proteins, which coordinate the specific “maps” axons and dendrites end up with. One of these microtubule-associated proteins, tau, has become quite well-known for malfunctioning and creating neurofibrillary tangles in Alzheimer’s disease. 1
How to ‘grow’ a microtubule
One may expect that such a rigid and complex structure must be difficult to generate. Indeed, they do not appear on their own – in fact, solutions of alpha-beta dimers do not self-assemble into microtubules unless the concentrations are very high. Far from being a deficit, this only means that cells have control of when and where they generate their microtubules, rather than them forming spontaneously wherever the building blocks exist.
Creating a new microtubule involves the process of nucleation (a term you may associate with clouds – which form when wet air cools and water droplets start to nucleate from the supersaturated air). Specialized machinery is needed to trigger this process, generally associated with a third type of tubulin – gamma. A gamma-tubulin ring acts as both a starting point and a template, on which alpha-beta units then start to assemble until they generate a fully-grown microtubule.2
Microtubules and memory
Microtubules, microtubule-associated proteins, and other cytoskeletal components have been involved in a variety of pathological conditions – from neurodevelopmental disorders, where neurons don’t migrate properly to where they are supposed to get, to neurodegenerative ailments, where proper neuronal dynamics seem to be lost. Let’s focus on another perspective though, and consider why and where the cytoskeleton and microtubules changing a neuron’s shape may hold a place in the healthy brain.
Microtubules appear to be especially dynamic in dendrites, polymerizing directly into particularly small ramifications called dendritic spines. With neurons being otherwise relatively stable structures, one theory suggests that such a dynamic nature may play a role in synaptic plasticity. Synaptic plasticity defines changes in synapses, in regards to shape but also molecular composition, which are thought to be the substrate for learning and memory.
Several recent experiments have explored the role microtubules play in synaptic plasticity. It turns out that blocking the dynamic instability of microtubules (either the lengthening or shortening aspect of it) abrogates synaptic plasticity in cultured neurons. This was further confirmed in mice. Blocking microtubule polymerization made mice perform worse in conditioned fear experiments (learning to associate fear to a specific stimulus). 3
Further attempts at gaining a finer level of control over microtubule dynamics and figuring out the precise role spines play are underway at the moment. Preliminary studies suggest there may be an interaction taking place between the dynamic microtubules which extend into dendritic spines and the rest of a spine’s cytoskeleton. Microtubules may, then, provide their highway role to allow for the transport of essential components in the process of gaining plasticity. Extensive studies are needed to elucidate the full picture here.
Nevertheless, it would be curious to see whether stabilizing microtubules may help diseases such as Alzheimer’s or Parkinson’s. Indeed, a relatively new drug, called EpoD, has ameliorated axonal dysfunction and cognitive deficits in two different Alzheimer’s mice models. Unfortunately, a clinical trial with the same drug yielded little benefits for Alzheimer’s patients. Nevertheless, this remains an interesting prospect for future therapies. 3
Ultimately, microtubules, as part of the neuronal cytoskeleton, do exactly what is suggested (provide a backbone), and so much more. Through their rapid adaptability, they turn neurons from a bundle of complex interrelated segments into functional, dynamic pieces of biological machinery. More than just wires or highways, they may well be essential for all cognitive processes and quite literally shape the way we think.
Resources:
- Kandel, E., Schwartz, J., Jessell, T., Siegelbaum, S. & Hudspeth, A. J. Principles of Neural Science. (Elsevier, 2012).
- Goodson, H. V. & Jonasson, E. M. Microtubules and microtubule-associated proteins. Cold Spring Harb. Perspect. Biol. 10, (2018).
- Dent, E. W. Of microtubules and memory: Implications for microtubule dynamics in dendrites and spines. Molecular Biology of the Cell 28, 1–8 (2017).
