A Stochastic Multiscale Model that Explains the Segregation of Axonal Microtubules and Neurofilaments in Neurological Diseases

TL;DR

This paper introduces a stochastic multiscale model explaining how impaired neurofilament transport and organelle interactions cause segregation of microtubules and neurofilaments in axons, shedding light on neurodegenerative disease mechanisms.

Contribution

The study develops a novel stochastic model that links organelle interactions and transport impairment to cytoskeletal segregation in axons, providing a mechanistic explanation for neurodegenerative pathology.

Findings

Organelle pulling causes microtubule-neurofilament segregation in hours.

Segregation depends on organelle size and traffic density.

Model predictions are experimentally testable.

Abstract

The organization of the axonal cytoskeleton is a key determinant of the normal function of an axon, which is a long thin projection away from a neuron. Under normal conditions two axonal cytoskeletal polymers microtubules and neurofilaments align longitudinally in axons and are interspersed in axonal cross-sections. However, in many neurotoxic and neurodegenerative disorders, microtubules and neurofilaments segregate apart from each other, with microtubules and membranous organelles clustered centrally and neurofilaments displaced to the periphery. This striking segregation precedes abnormal and excessive neurofilament accumulation in these diseases, which in turn leads to focal axonal swellings. While neurofilament accumulation suggests the impairment of neurofilament transport along axons, the underlying mechanism of their segregation from microtubules remains poorly understood for over 30 years. To address this question, we developed a stochastic multiscale model for the cross-sectional distribution of microtubules and neurofilaments in axons. The model describes microtubules, neurofilaments and organelles as interacting particles in a 2D cross-section, and incorporates the stochastic interactions these particles through molecular motors. Simulations of the model demonstrate that organelles can pull nearby microtubules together, and in the absence of neurofilament transport, this mechanism gradually segregates microtubules from neurofilaments on a time scale of hours, similar to that observed in toxic neuropathies. This suggests that the microtubule-neurofilament segregation is simply a consequence of the selective impairment of neurofilament transport. The model generates the experimentally testable prediction that the rate and extent of segregation will be dependent on the sizes of the moving organelles as well as the density of their traffic.