Neurodegeneration and microtubule dynamics: death by a thousand cuts

Abstract

Microtubules form important cytoskeletal structures that play a role in establishing and maintaining neuronal polarity, regulating neuronal morphology, transporting cargo, and scaffolding signaling molecules to form signaling hubs. Within a neuronal cell, microtubules are found to have variable lengths and can be both stable and dynamic. Microtubule associated proteins, post-translational modifications of tubulin subunits, microtubule severing enzymes, and signaling molecules are all known to influence both stable and dynamic pools of microtubules. Microtubule dynamics, the process of interconversion between stable and dynamic pools, and the proportions of these two pools have the potential to influence a wide variety of cellular processes. Reduced microtubule stability has been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and tauopathies like Progressive Supranuclear Palsy. Hyperstable microtubules, as seen in Hereditary Spastic Paraplegia (HSP), also lead to neurodegeneration. Therefore, the ratio of stable and dynamic microtubules is likely to be important for neuronal function and perturbation in microtubule dynamics might contribute to disease progression.

Keywords: Alzheimer's disease; Parkinson disease; dying back; hyperstable microtubules; microtuble stability; microtubule signaling hubs.

Figure 1

Proteins and modifications associated with unstable and stable microtubules. (A) Shrinking microtubules disassemble from their plus ends, lose their MAPs, are not acetylated but are tyrosinated. LRRK2 binds to the luminal side of β-Tubulin and prevents acetylation of microtubules. (B) Stable microtubules have a large complement of proteins associated with them, are not tyrosinated, are acetylated and have GTP-capped ends with multiple proteins. (C) Plus-ends of microtubules have several +TIP proteins. Several bind to the plus end binding EB proteins and GTP bound β-Tubulin. The precise location of DLK binding on microtubules is unknown. α-Tubulin (), β-Tubulin (), GTP bound β-Tubulin (), α/β heterodimer (), Kinesin motor (), Dynein motor (). Present on less stable microtubules: Tyrosination (), Gαs (), LRRK2 (). Present on stable microtubules: MAP1 (axon and dendrites) (), TAU (axon) (), MAP2 (), Acetylation (), Gβγ (), +end binding proteins (). Proteins present on the +end or fast growing end of microtubules (+TIPs): EBP1/2/3 (), CLIP170 (), CLASPS (), APC (), RHO GEF2 (), MACF ().

Figure 2

Ratios of stable and dynamic microtubule alter neuronal structure and function. (A) Healthy neurons have short and long, stable, and dynamic microtubules (B) Increased numbers of dynamic microtubules lead to increased neuronal branching, synapse retraction, and reduced axonal transport. This eventually can lead to dying-back neuropathy. (C) Hyperstable microtubules increase the diameter of the neuron, inhibit neurite outgrowth, and inhibit neuronal branching. Stable microtubule (), depolymerzing microtubule (), microtubule associated proteins (), microtubule plus end binding proteins (), mitochondria (), membranous cargo (), non-membranous cargo (), Kinesin motor (), Dynein motor (), Actin filaments (), Actin bundles (), neurotransmitters (), channels (), neurotransmitter receptors ().