Simulation of Traffic Jam Formation in Fast Axonal Transport

Author(s):  
A. V. Kuznetsov ◽  
A. A. Avramenko ◽  
D. G. Blinov

Many neurodegenerative diseases, such as Alzheimer’s disease, are linked to swellings occurring in long arms of neurons. Many scientists believe that these swellings result from traffic jams caused by the failure of intracellular machinery responsible for fast axonal transport; such traffic jam can plug an axon and prevent the sufficient amount of organelles to be delivered toward the synapse of the axon. Mechanistic explanation of the formation of traffic jams in axons induced by overexpression of tau protein is based on the hypothesis that the traffic jam is caused not by the failure of molecular motors to transport organelles along individual microtubules but rather by the disruption of the microtubule system in an axon, by the formation of a swirl of disoriented microtubules at a certain location in the axon. This paper investigates whether a microtubule swirl itself, without introducing into the model microtubule discontinuities in the traffic jam region, is capable of capturing the traffic jam formation. The answer to this question can provide important insight into the mechanics of the formation of traffic jams in axons.

Author(s):  
Andrey V. Kuznetsov

This paper simulates effects of structural changes in the microtubule (MT) system on mass transfer in an axon. Understanding this process is important for understanding the underlying reasons for many neurodegenerative diseases, such as Alzheimer’s disease. In particular, it is investigated how the degree of polar mismatching in an MT swirl affects organelle trap regions in the axon and inhibiting transport of organelles down the axon. The model is based on modified Smith-Simmons equations governing molecular-motor-assisted transport in neurons. It is established that the structure that develops as a result of a region with disoriented MTs (the MT swirl) consists of two organelle traps, the trap to the left of the swirl region accumulates plus-end oriented organelles and the trap to the right of this region accumulates minus-end oriented organelles. The presence of such a structure is shown to decrease the transport of organelles toward the synapse of the axon. Four cases with a different degree of polar mismatching in the swirl region are investigated; the results are compared with simulations for a healthy axon, in which case organelle traps are absent.


2002 ◽  
Vol 2 (2) ◽  
pp. 151-166 ◽  
Author(s):  
Dick Terwel ◽  
Ilse Dewachter ◽  
Fred Van Leuven

2004 ◽  
Vol 25 ◽  
pp. S428
Author(s):  
Wendy J. Noble ◽  
Michelle A. Utton ◽  
Brian H. Anderton ◽  
Diane P. Hanger

2010 ◽  
Vol 133 (1) ◽  
Author(s):  
A. V. Kuznetsov

This paper develops a model for simulating transport of newly synthesized material from the neuron body toward the synapse of the axon as well as transport of misfolded and aggregated proteins back to the neuron body for recycling. The model demonstrates that motor-assisted transport, much similar to diffusion, can occur due to a simple concentration difference between the cell body and the synapse; organelles heading to the synapse do not need to attach preferably to plus-end-directed molecular motors, same as organelles heading to the neuron body for recycling do not need to attach preferably to minus-end-directed molecular motors. The underlying mechanics of molecular-motor-assisted transport is such that organelles would be transported to the right place even if new and used organelles had the same probability of attachment to plus-end-directed (and minus-end-directed) motors. It is also demonstrated that the axon with organelle traps and a region with a reversed microtubule polarity would support much smaller organelle fluxes of both new and used organelles than a healthy axon. The flux of organelles is shown to decrease as the width of organelle traps increases.


Open Physics ◽  
2011 ◽  
Vol 9 (1) ◽  
Author(s):  
Andrey Kuznetsov

AbstractThis paper formulates a four kinetic state model for fast axonal transport. The paper further develops the Smith-Simmons model that is based on equations governing intracellular molecular-motor-assisted transport; these equations are extended by considering four rather than three kinetic states for organelles. The model considers plus-end and minus-end-oriented organelles that can be either free (suspended in the cytosol) or attached to microtubules (MTs) (in the latter case organelles are transported by molecular motors). The paper then develops a method for uncoupling differential equations of the proposed model. A perturbation solution of this problem is obtained. The effect of transition between plus-end-oriented and minus-end oriented organelles is discussed. The accuracy of the obtained perturbation solution is evaluated by comparing the zero-order and the first-order results with a high-accuracy numerical solution.


2020 ◽  
Author(s):  
Viktor K. Lund ◽  
Matthew D. Lycas ◽  
Anders Schack ◽  
Rita C. Andersen ◽  
Ulrik Gether ◽  
...  

SUMMARYLong range fast axonal transport of neuropeptide-containing dense core vesicles (DCVs), endolysosomal organelles and presynaptic components is critical for maintaining the functionality of neurons. How the transport of DCVs is orchestrated remains an important unresolved question. The small GTPase Rab2 has previously been shown to mediate DCV biogenesis and endosome-lysosome fusion. Here we use the Drosophila model system to demonstrate that Rab2 also plays a critical role in bidirectional axonal transport of DCVs, endosomes and lysosomal organelles, most likely by controlling molecular motors. We further show that the lysosomal motility factor Arl8 is required as well for axonal transport of DCVs, but unlike Rab2 is also critical for DCV exit from cell bodies into axons. Our results uncover the mechanisms responsible for axonal transport of DCVs and reveal surprising parallels between the regulation of DCVs and lysosomal motility.


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