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Date of Award
Neurofilaments (NFs) are important cytoskeletal filaments that maintain the mechanical stability of axons through interactions mediated by side arms and their phosphorylation. Researchers have provided conflicting descriptions of the role of phosphorylation on medium (NF-M) and heavy (NF-H) neurofilaments regarding axonal diameter. Initially axonal growth was said to be dependent on NF-H; later NF-M was described as essential. Thereafter it was shown that NF-M phosphorylation does not affect axonal caliber. This thesis investigates these apparently contradictory results computationally using a NF brush model that captures the entropic and electrostatic interactions between the amino acids, while also representing the stoichiometry of the neurofilaments. Mouse neurofilaments are first modeled, and compared to a human neurofilament model. As the mouse model results could be explained well in comparison with the human results, the model was changed appropriately to enable comparison with experimental results. Simulations were performed in a salt-free environment and in a 100 mM ionized solution. Both simulations confirm that the axonal diameter in mouse neurofilaments is not dependent on NF-M phosphorylation. However, the extension of NF-H is dependent on phosphorylation in both simulations, and is larger than the NF-M extension. Thus NF-H may bound the axonal diameter of mouse neurofilaments. This contradicts previous findings on the importance of NF-H.
Stevenson, William John, "Phosphorylation‐mediated conformational changes in mouse neurofilament architecture: insight from a computational model" (2011). Wayne State University Theses. 81.