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

Abstract

The organization of the axonal cytoskeleton is a key determinant of the normal function of an axon, which is a long thin projection of 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 the abnormal and excessive neurofilament accumulation in these diseases, which in turn leads to focal axonal swellings. While neurofilament accumulation suggests an 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 is built upon molecular processes that occur on a time scale of seconds or shorter. It incorporates the longitudinal transport of neurofilaments and organelles through this domain by allowing stochastic arrival and departure of these cargoes, and integrates the dynamic interactions of these cargoes with microtubules mediated by 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 can be 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.

Intermediate filament accumulation can stabilize microtubules inCaenorhabditis elegansmotor neurons

“…Since we found that loss of IFs in tba-1(gf) dlk-1(0) animals could restore MT dynamics and promote synapse rewiring, we next wanted to test if pharmacologically manipulating IF assembly would result in a similar phenotype. 2,5-Hexanedione (2,5-HD) is a metabolite of the industrial solvent hexane that causes IF disruption upon application to cultured mammalian cells and alters NF interaction with MTs in mammalian axons, although the precise mechanism of 2,5-HD action is unclear (33)(34)(35). We first characterized the effects of 2,5-HD exposure on C. elegans IF assembly using IFP-1::GFP.…”

The Spectrum of Mechanism-Oriented Models and Methods for Explanations of Biological Phenomena

“…Increasing complexity in pursuit of mechanism-oriented models that improve explanatory credibility is an explicit strategy within biology simulation research (e.g., see [27,45,47]). For the larger community of biologists, a priority is achieving deeper, more useful explanations of phenomena that facilitate advancing both science and health.…”

Neuroinformatics and Computational Modelling as Complementary Tools for Neurotoxicology Studies

“…Examples of neurotoxicology testing by in silico models could potentially include at least the following topics and research areas: (i) models for assessing chemical effects on neurodevelopment, neurite outgrowth and organization of axonal cytoskeleton ; (ii) models for studying the functional consequences of altered receptor ion channel dynamics on the excitability of various neural cell types, including both neuronal and glial cells, in the CNS and PNS ; and (iii) in vivo neurotoxic effects of various toxins and compounds in the cortical and other CNS networks. Some research has already been conducted with in silico modelling in these neurotoxicology research topics.…”

“…The shape and function of axons are dependent on a dynamic system of microscopic intracellular protein polymers (microtubules, neurofilaments and microfilaments) that comprise the axonal cytoskeleton. This organization of the cytoskeleton was studied with a stochastic multiscale model for the cross‐sectional distribution of microtubules and neurofilaments in axons . The model demonstrates that organelles can pull nearby microtubules together, and in the absence of neurofilament transport, this mechanism gradually segregates microtubules from neurofilaments on a timescale of hours.…”