Regulation of Axonal Neurofilament Dynamics by Phosphorylation

University Of Massachusetts Lowell, Lowell MA

Investigators

Abstract

Neurons, the cells of the brain that allow us to think, feel and move, have a very unique shape, which is referred to as "polarized." Extending from one side of the neuron are many fingerlike extensions ("dendrites") that receive information from other neurons, and extending from the other side is a longer extension (the "axon") that transmits the sum of this information to the next neuron. How neurons assume this unique polarized form, and then maintain it for the lifetime of an individual, is not entirely clear. However, it is dependent at least in part upon a fibrous network of proteins referred to as the "cytoskeleton." This network forms a sort of skeleton for the neuron, which helps it maintain its shape. Unlike bones, however, the parts of the cytoskeleton are constantly replaced. This poses a difficult situation for neurons, since all proteins are synthesized in the cell body, and then must be assembled and transported into and along axons by a process called "axonal transport." This process must be highly regulated, or the proteins will assemble incorrectly, or clump up within the beginning of the axon, and the neuron may die. In some neurons, axonal transport must be carried out over long distances. For example, the sciatic nerve, which runs all the way down our leg, receives all of its cytoskeletal proteins from a small cell body near the spine. Our studies examine how the neuron regulates axonal transport of one set of cytoskeletal proteins called neurofilaments. The neuron has a set of modifying enzymes, called "kinases," that reversibly modify the neurofilaments. One simple analogy for such modifications is to put a cap on a pen. When the pen is capped, its writing function is altered. When the cap is removed, its function is restored. Rather than having to synthesize a new pen every time we need to write, we instead cap the pen until it is needed again. Kinases similarly turn various protein functions on and off. Our ongoing studies indicate that these modifications regulate how neurofilaments assemble, undergo axonal transport, and provide structural support to axons, and that certain modifications switch the neurofilaments from transporting along axons to instead interacting with other neurofilaments to form a strong bundle that supports the axon. Using genetically-engineered kinases and neurofilament proteins, we will monitor these changes. These studies will provide important information about axonal transport and stabilization.