Regulation of Axonal Neurofilament Dynamics by Phosphorylation

神经元是大脑中让我们思考、感觉和运动的细胞，它有一个非常独特的形状，被称为“极化”。从神经元的一侧延伸出来的是许多指状的延伸部分（“树突”），它们接收来自其他神经元的信息，而从另一侧延伸出来的是一个更长的延伸部分（“轴突”），它将这些信息的总和传递给下一个神经元。 神经元如何呈现这种独特的极化形式，然后在个体的一生中保持它，并不完全清楚。 然而，它至少部分依赖于被称为“细胞骨架”的蛋白质纤维网络。“这个网络形成了神经元的一种骨架，帮助它保持形状。 然而，与骨骼不同的是，细胞骨架的各个部分不断地被替换。 这给神经元带来了困难，因为所有的蛋白质都是在细胞体中合成的，然后必须通过称为“轴突运输”的过程组装并沿着轴突运输。“这个过程必须受到高度调控，否则蛋白质将错误地组装，或者在轴突的开始处聚集，神经元可能会死亡。 在某些神经元中，轴突运输必须进行长距离。例如，我们的坐骨神经从脊柱附近的一个小细胞体接收所有的细胞骨架蛋白，我们的研究检查了神经元如何调节一组称为神经丝的细胞骨架蛋白的轴突运输。 神经元有一组称为“激酶”的修饰酶，它们可逆地修饰神经丝。 这种修改的一个简单类比是给钢笔戴上笔帽。 当笔被加盖时，其书写功能被改变。 当盖被移除时，其功能恢复。 我们不必每次需要书写时都合成一支新笔，而是将笔盖上，直到再次需要它。 激酶类似地开启和关闭各种蛋白质功能。 我们正在进行的研究表明，这些修饰调节神经丝如何组装、进行轴突运输并为轴突提供结构支持，并且某些修饰将神经丝从沿着轴突运输转变为与其他神经丝相互作用以形成支持轴突的强束。 使用基因工程激酶和神经丝蛋白，我们将监测这些变化。 这些研究将提供重要的信息轴突运输和稳定。

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.