The Role of Spastin in Axon Biology

Abstract

Neurons are highly polarized cells with elaborate shapes that allow them to perform their function. In neurons, microtubule organization-length, density, and dynamics-are essential for the establishment of polarity, growth, and transport. A mounting body of evidence shows that modulation of the microtubule cytoskeleton by microtubule-associated proteins fine tunes key aspects of neuronal cell biology. In this respect, microtubule severing enzymes-spastin, katanin and fidgetin-a group of microtubule-associated proteins that bind to and generate internal breaks in the microtubule lattice, are emerging as key modulators of the microtubule cytoskeleton in different model systems. In this review, we provide an integrative view on the latest research demonstrating the key role of spastin in neurons, specifically in the context of axonal cell biology. We focus on the function of spastin in the regulation of microtubule organization, and axonal transport, that underlie its importance in the intricate control of axon growth, branching and regeneration.

Keywords: axon growth; axon regeneration; axonal cytoskeleton; axonal transport; microtubule severing enzyme; microtubules; spastin.

FIGURE 1

Spastin at pre- and post-synaptic sites (A) At axonal en passant synapses, the axonal transport of synaptic vesicles is dependent on the increase dynamics of MTs. Due to the weak affinity of kinesin-3 to MT GTP-bound tubulin, these molecular motors detach from MTs when they encounter their dynamic plus-ends, releasing transported cargoes within the synapse. The mechanisms underlying increase MT dynamics at these sites are currently under investigation. Due to its role in MT dynamics, the control of spastin activity at axon pre-synapses might contribute to generate a pool of dynamic MTs (B) At post-synapses, spastin indirectly modulates the transport of synaptic vesicles and AMPA receptors through the control of tubulin polyglutamylation levels. Loss of spastin increases tubulin polyglutamylation levels, decreasing the binding affinity of KIF5, leading to transport impairments.

FIGURE 2

Spastin plays a vital role in regulating MT cytoskeleton density and dynamics. We propose that in wild-type animals, endogenous spastin contributes to the maintenance of a dynamic and dense MT cytoskeleton that sustains an efficient axonal transport. Its activity may increase the number of dynamic MTs, facilitating the loading of retrograde cargoes mediated through dynein motors. In the absence of spastin, the density and dynamics of MTs is reduced, due to a decline in the levels of MT severing and MT nucleation, decreasing the overall axonal transport.

FIGURE 3

Spastin modulates axon branching and (re)growth through MT dependent and independent mechanisms. Spastin severing activity may increase the availability of short and dynamic MTs that are anterogradely transported towards (A) growth cones and (B) axonal branches, supporting axon elongation at these sites. Of note, spastin is highly concentrated at these sites (Yu et al., 2008) (C) Spastin regulates the transport of the growth-related molecule Rab11 by interacting with the ER protein protrudin. In CNS, overexpression of protrudin leads to robust CNS regeneration (Petrova et al., 2020) (D) The movement of ER through the tip attachment complex is mediated by the binding of ER to the protein complex STIM1 and EB1 at the plus-tip of MTs. Upon injury, the ER accumulates at growth cones of regenerating axons (Rao et al., 2016). We propose that an increase of spastin after injury, may increase the number of MT plus-tips, which might underlie the increment in the transport of ER to these axonal sites.