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Computational Modeling of Slow Neurofilament Transport along Axons

Nguyen, Tung Le
http://orcid.org/0000-0003-4421-1101
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1547036394834075

Abstract Details

2019, Doctor of Philosophy (PhD), Ohio University, Physics and Astronomy (Arts and Sciences).
Neurofilaments are abundant space-filling cytoskeletal polymers that accumulate in myelinated axons during development to drive the expansion of axon caliber, which is a key determinant of axonal conduction velocity [2, 39]. Neurofilaments are also cargoes of axonal transport that are assembled predominantly in the cell body and move out along axons on microtubule tracks powered by microtubule motor proteins [4]. This dual role of neurofilaments as space-filling structures and cargoes of axonal transport implies a complex relationship between axon caliber, neurofilament influx from the cell body, and neurofilament transport kinetics in the axon. Axonal injury present a good model system to study the role of neurofilament flux for transport velocity and axon caliber, because of the wealth of available morphometric and kinetic data [13, 23]. After injury, retrogradely transported injury signals trigger a transient reduction in neurofilament gene expression in the cell body and a corresponding transient reduction in neurofilament influx into the axon, resulting in a wave of axon thinning that propagates distally at a rate consistent with neurofilament transport [13]. Coincident with these changes, radioisotopic pulse labeling studies have revealed a transient increase the average neurofilament transport velocity [23]. Neurofilament kinetics near the nodes of Ranvier of myelinated axons is a model system probing the role of local changes of the transport machinery of neurofilaments for sculpting the characteristic nodal constrictions. Myelinated axons are wrapped by myelin sheaths, interrupted by short segments of a few microns where most ion channels important for the conduction of action potentials are located. Depending on the size of the axon, the diameter of the axon is significantly reduced at the nodes of Ranvier forming nodal constrictions, along which the number of neurofilaments is reduced, forming a bottleneck for axonal transport. The question addressed here is how neurofilaments navigate this bottle neck without forming traffic jams and causing axonal swelling. To answer this question, we developed a new computational model for axonal transport of neurofilaments in which neurofilament motility is related to the organization of the axonal cytoskeleton, in particular the microtubule tracks along which they are transported. Using this new model in the study of axonal injury, we can explain the time-course of post-injury decrease of axon caliber and increase in neurofilament transport velocity by a simple reduction of neurofilament flux, and the subsequent time-course of axonal recovery by a corresponding recovery of neurofilament flux. These findings demonstrate that proximity of neurofilaments to microtubules may be a key determinant of their motility. One important prediction of this model is that average neurofilament transport velocity and axon caliber are sensitive to small changes in neurofilament and microtubule density and organization. Applying our new model, we can predict the formation of a nodal constriction, where the local neurofilament kinetics and the morphology of the constricted axon are in good agreement with morphometric and kinetic data. In summary, our computational research has resulted in a predictive conceptual model framework to better understand the complex relationship between neurofilament kinetics and axon morphology. We believe that these insights have important implications for the mechanisms by which neurofilaments accumulate in axons during development, and contribute to pathological accumulations of neurofilaments observed in a host of neurodegenerative diseases (such as Charcot - Marie - Tooth disease).
Peter Jung (Advisor)
David Tees (Committee Member)
175 p.
Biology; Neurosciences; Physics
axonal transport

Recommended Citations

Citations

  • Nguyen, T. L. (2019). Computational Modeling of Slow Neurofilament Transport along Axons [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1547036394834075

    APA Style (7th edition)

  • Nguyen, Tung. Computational Modeling of Slow Neurofilament Transport along Axons. 2019. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1547036394834075.

    MLA Style (8th edition)

  • Nguyen, Tung. "Computational Modeling of Slow Neurofilament Transport along Axons." Doctoral dissertation, Ohio University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1547036394834075

    Chicago Manual of Style (17th edition)

ohiou1547036394834075
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This open access ETD is published by Ohio University and OhioLINK.