Callan-Jones, A. | bioRxiv Science

bioRxiv2019

The roles of microtubules and membrane tension in axonal beading, retraction, and atrophy

Axonal beading--formation of a series of swellings along the axon--and retraction are commonly observed shape transformations that precede axonal atrophy in Alzheimers, Parkinson, and other neurodegenerative conditions. The mechanisms driving these morphological transformations are poorly understood. Here we report controlled experiments which can induce either beading or retraction and follow the time evolution of these responses. By making quantitative analysis of the shape modes under different conditions, measurement of membrane tension, and using theoretical considerations, we argue that membrane tension is the main driving force that pushes cytosol out of the axon when microtubules are degraded, causing axonal thinning. Under pharmacological perturbation, atrophy is always retrograde and this is set by a gradient in the microtubule stability. The nature of microtubule depolymerization dictates the type of shape transformation vis a vis beading or retraction. Elucidating the mechanisms of these shape transformations will facilitate development of strategies to prevent or arrest axonal atrophy due to neurodegenerative conditions.

biophysics↗

bioRxiv2019

The axonal actin-spectrin lattice acts as shock absorbers to protect neurons from stretch-induced damage

Axons are thin tubular extensions generated by neuronal cells to transmit signals across long distances. In the peripheral and the central nervous systems, axons experience large deformations during normal activity or as a result of injury. Yet, axon biomechanics, and its relation to the internal structure that allows axons to withstand such deformations, is poorly understood. Up to now, it has been generally assumed that microtubules and their associated proteins are the major load-bearing elements in axons. We revise this view point by combining mechanical measurements using a custom developed force apparatus with biochemical or genetic modifications to the axonal cytoskeleton, revealing an unexpected role played by the actin-spectrin skeleton. For this, we first demonstrate that axons exhibit a reversible 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, and show that the recently discovered membrane-associated skeleton consisting of periodically spaced actin filaments interconnected by spectrin tetramers play a prominent mechanical role. Finally, using a theoretical model we argue that the actin-spectrin skeleton act as an axonal tension buffer by reversibly unfolding repeat domains of the spectrin tetramers to buffer excess mechanical stress.

biophysics↗