The axonal actin-spectrin lattice acts as a tension buffering shock absorber

Abstract

Axons span extreme distances and are subject to significant stretch deformations during limb movements or sudden head movements, especially during impacts. Yet, axon biomechanics, and its relation to the ultrastructure that allows axons to withstand mechanical stress, is poorly understood. Using a custom developed force apparatus, we demonstrate that chick dorsal root ganglion axons exhibit a tension buffering or strain-softening response, where its steady state elastic modulus decreases with increasing strain. We then explore the contributions from the various cytoskeletal components of the axon to show that the recently discovered membrane-associated actin-spectrin scaffold plays a prominent mechanical role. Finally, using a theoretical model, we argue that the actin-spectrin skeleton acts as an axonal tension buffer by reversibly unfolding repeat domains of the spectrin tetramers to release excess mechanical stress. Our results revise the current viewpoint that microtubules and their associated proteins are the only significant load-bearing elements in axons.

A common theme for axonopathies? The dependency cycle of local axon homeostasis

“…Further important roles are played by the axonal cortex which provides architectural support and also influences MT polymerisation behaviours ('4' in Figure 2a; Datar et al, 2019;Dubey et al, 2020;Qu, Hahn, Webb, Pearce, & Prokop, 2017;Wang et al, 2020). These cortical properties might explain brain disorders This scenario where MT bundle-damage due to life-sustaining axonal transport is counterbalanced by bundle-maintaining actions of MTBPs and the cortex, could be an essential pillar of axon maintenance and has originally been formulated in our model of 'local axon homeostasis' (Hahn et al, 2019).…”

Cytoskeletal organization of axons in vertebrates and invertebrates

“…The axonal cytoskeleton of invertebrates and vertebrates alike shows conserved features, such as central longitudinal F-actin trails and cortical F-actin rings arranged by spectrins into a periodic pattern ( Xu et al, 2013 ; Leterrier et al, 2017a ). Of these, the actin rings seem to have important roles in regulating axonal stiffness ( Krieg et al, 2017 ; Dubey et al, 2020 ), axon diameter ( Costa et al, 2018 , 2020 ) and microtubule (MT) polymerization ( Qu et al, 2017 ). MTs of various lengths are organized into longitudinal parallel bundles that run along axons, often accompanied by intermediate filaments (neurofilaments [NFs]).…”

Molecular and Cellular Mechanisms Affected in ALS

“…Neurofilaments form cross-bridges not only with each other but, also, with actin filaments, actin rings, and microtubules [ 114 ], constituing a protein network that might participate to the maintenance of the axon structure [ 114 , 116 ]. Actin polymerization requires the small actin-binding proteins profilin I and II and phosphoinositide islands localized at the membrane [ 117 ].…”