Microtubule Polymerization and Cross-Link Dynamics Explain Axonal Stiffness and Damage.

Axonal damage is a critical indicator for traumatic effects of physical impact to the brain. However, the precise mechanisms of axonal damage are still unclear. Here, we establish a mechanistic and highly dynamic model of the axon to explore the evolution of damage in response to physical forces. Our axon model consists of a bundle of dynamically polymerizing and depolymerizing microtubules connected by dynamically detaching and reattaching cross-links. Although the probability of cross-link attachment depends exclusively on thermal fluctuations, the probability of detachment increases in the presence of physical forces. We systematically probe the landscape of axonal stretch and stretch rate and characterize the overall axonal force, stiffness, and damage as a direct result of the interplay between microtubule and cross-link dynamics. Our simulations reveal that slow loading is dominated by cross-link dynamics, a net reduction of cross-links, and a gradual accumulation of damage, whereas fast loading is dominated by cross-link deformations, a rapid increase in stretch, and an immediate risk of rupture. Microtubule polymerization and depolymerization decrease the overall axonal stiffness, but do not affect the evolution of damage at timescales relevant to axonal failure. Our study explains different failure mechanisms in the axon as emergent properties of microtubule polymerization, cross-link dynamics, and physical forces. We anticipate that our model will provide insight into causal relations by which molecular mechanisms determine the timeline and severity of axon damage after a physical impact to the brain.