How Does Phosphorylation Regulate Neurofilament Transport?

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This EAGER project aims to address a controversy regarding the role of phosphorylation on neurofilament (NF) transport. Neurofilament phosphorylation has long been considered to regulate their axonal transport rate and in doing so to provide stability to mature axons. Phosphorylation of the C-terminal extension of the largest (NFH) of the 3 NF subunits is classically thought to slow NF transport. This project proposes that phosphorylation inhibits transport by fostering NF-NF associations leading to formation of NF bundles too large to transport. Other approaches involving NF subunit knockout or truncation have advanced the notion that phosphorylation does not regulate transport. This project is set out to address this controversy by expressing the NF-H sidearm in transfected cells. They will manipulate cdk5 activity to alter sidearm phosphorylation and monitor the influence on association with NF bundles. The proposed experiments should provide the first direct comparison of the impact of sidearm phosphorylation without the complications that have compromised prior studies. The project will provide training and mentoring of undergraduate and graduate students, fostering their publications, and introduce them to the scientific community at large by supporting their attendance at international meetings. This research also has broad impacts regarding the field of cell biology, in that it will continue to provide novel information regarding the "load-bearing" aspect of intermediate filaments in all cell types.