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.
Highlights
Axons are long slender projections of nerve cells that permit fast and specific electrical communication with other cells over long distances
The shape and function of axons is dependent on a dynamic system of microscopic intracellular protein polymers that comprise the axonal cytoskeleton
Neurofilaments are cargoes of intracellular transport that move along microtubule tracks, and they accumulate abnormally in axons in many neurotoxic and neurodegenerative disorders
Summary
Axons are long slender projections of nerve cells that permit fast and specific electrical communication with other cells over long distances. Microtubules are stiff hollow cylindrical structures about 25 nm in diameter that serve as tracks for the long-range bidirectional movement of intracellular membranous organelles and macromolecular cargo complexes In axons, this movement is known as axonal transport [3]. Neurofilaments, which are the intermediate filaments of nerve cells, are flexible rope-like polymers that measure about 10 nm in diameter [5]. These polymers function as space-filling structures that expand axonal cross-sectional area, thereby maximizing the rate of propagation of the nerve impulse [6, 7]. Mutant animals that lack neurofilaments develop smaller caliber axons and exhibit delayed conduction velocities [9,10,11]
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