Elsevier

Brain Research Bulletin

Volume 126, Part 3, September 2016, Pages 217-225
Brain Research Bulletin

Research report
Microtubules in health and degenerative disease of the nervous system

https://doi.org/10.1016/j.brainresbull.2016.06.016Get rights and content

Highlights

  • Microtubules are essential for development and maintenance of axons and dendrites.

  • Microtubules are vulnerable in a variety of neurodegenerative diseases.

  • Dysfunctional microtubules are at the center of neurodegeneration and injury.

  • Microtubules undergo complex modifications and protein-protein interactions.

  • Microtubule-mediated mechanisms are ripe with therapeutic targets.

Abstract

Microtubules are essential for the development and maintenance of axons and dendrites throughout the life of the neuron, and are vulnerable to degradation and disorganization in a variety of neurodegenerative diseases. Microtubules, polymers of tubulin heterodimers, are intrinsically polar structures with a plus end favored for assembly and disassembly and a minus end less favored for these dynamics. In the axon, microtubules are nearly uniformly oriented with plus ends out, whereas in dendrites, microtubules have mixed orientations. Microtubules in developing neurons typically have a stable domain toward the minus end and a labile domain toward the plus end. This domain structure becomes more complex during neuronal maturation when especially stable patches of polyaminated tubulin become more prominent within the microtubule. Microtubules are the substrates for molecular motor proteins that transport cargoes toward the plus or minus end of the microtubule, with motor-driven forces also responsible for organizing microtubules into their distinctive polarity patterns in axons and dendrites. A vast array of microtubule-regulatory proteins impart direct and indirect changes upon the microtubule arrays of the neuron, and these include microtubule-severing proteins as well as proteins responsible for the stability properties of the microtubules. During neurodegenerative diseases, microtubule mass is commonly diminished, and the potential exists for corruption of the microtubule polarity patterns and microtubule-mediated transport. These ill effects may be a primary causative factor in the disease or may be secondary effects, but regardless, therapeutics capable of correcting these microtubule abnormalities have great potential to improve the status of the degenerating nervous system.

Introduction

The microtubule arrays of axons and dendrites provide a structural backbone that allows them to acquire and maintain their specialized morphologies. In addition to acting as structural elements, microtubules are long-distance railways for proteins and organelles to be actively transported in both directions within axons and dendrites. Microtubules are crucial for early developmental stages of the neuron, such as migration of the soma and the navigation of the growth cone at the tip of the elongating axon. Microtubules are also important throughout the life of the neuron, for it to maintain its proper morphology, to enable axonal and dendritic transport, and to accommodate morphological changes such as alterations in dendritic shape that may correspond with cognitive plasticity, even in old age. Proper functioning of microtubules and their assortment of interacting and regulatory proteins as well as regulatory pathways is crucial for the health of the nervous system. Abnormalities of the microtubule systems of axons and dendrites are a major contributor to neurodegenerative diseases. The purpose of this review is to provide a brief overview of contemporary knowledge of neuronal microtubules and how they may go awry during degeneration of the diseased nervous system.

Section snippets

Microtubule organization in neurons

Tubulin is a heterodimer of alpha tubulin and beta tubulin, each of which is a different primary gene product believed to have diverged evolutionarily from a single gene (Keeling and Doolittle, 1996). In vertebrates, there are multiple alpha tubulin genes and multiple beta tubulin genes. In the test tube, microtubules can be nucleated de novo if there is a sufficient concentration of free tubulin, as well as the presence of GTP and appropriate temperature and buffer conditions. In living cells,

Microtubule dynamics and stability in neurons

Microtubule dynamics in cells are governed by a mechanism known as dynamic instability (Mitchison and Kirschner, 1984, Drechsel et al., 1992, Waterman-Storer and Salmon, 1997, Burbank and Mitchison, 2006) that depends on tubulin being a GTPase. Free tubulin associates with hydrolysable GTP. Both alpha and beta tubulin associate with GTP, however the GTP bound to alpha tubulin rests in the region where alpha and beta tubulin interact. Therefore, tubulin heterodimers are only able to hydrolyze

Microtubule end-targeting proteins

+tips are proteins that associate with the plus end of the microtubule during bouts of assembly. Some have their own affinity for the plus end of the microtubule, by recognizing the GTP cap, while others have an affinity for other +tips and become +tips themselves for that reason. These proteins include EB1, EB3, CLIPs, CLASPs and others (Akhmanova and Hoogenraad, 2005). Fluorescently conjugated +tips are useful for live-cell imaging of microtubule assembly and organization in cells. In

Microtubule-severing proteins

Microtubule-related proteins are AAA enzymes that form hexamers on the surface of the microtubule. The hexamers yank on a tubulin subunit to extract it from the microtubule lattice, causing the microtubule to break (Roll-Mecak and Vale, 2006, Roll-Mecak and McNally, 2010). Such severing of microtubules can occur near their minus ends within the centrosome to release the microtubule so that it can then be transported into an axon or a dendrite. Severing can also occur at the plus end so that

The tubulin code

Why do cells so tightly regulate tubulin post-translational modifications that do not impose stability on microtubules directly, but often reflect their stability? A great deal of evidence suggests that post-translational modifications of tubulin impose a “code” on the microtubule that is read by other proteins (Garnham and Roll-Mecak, 2012, Yu et al., 2015). The idea is that many microtubule-related proteins have preferential affinities for microtubules (or domains of a microtubule) that are

Microtubule defects in nervous system disease

The various aspects of the neuronal microtubule arrays thus far discussed can be corrupted over the life of the neuron by the aging process as well as by neurodegenerative disease mechanisms. For example, the axon must preserve a nearly uniform polarity orientation of microtubules in order for the anterograde and retrograde transport of various cargoes to be properly orchestrated. Corruption of the microtubule polarity pattern (i.e., appearance of too many mal-oriented microtubules) would send

Acknowledgments

The work of the authors is currently supported by grants to PWB from the Craig H. Neilsen Foundation (Grant 259350), the National Institutes of Health (NIH; NINDS; Grant R01 NS28785), the Department of Defense (GW120037 and GW140086), and the State of Pennsylvania Tobacco Settlement Funds.

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