Regulation of Axonal Neurofilament Dynamics by Phosphorylation

通过磷酸化调节轴突神经丝动力学

• 批准号: 0217838
• 负责人: Thomas Shea
• 金额: --
• 依托单位: University of Massachusetts Lowell
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0217838&HistoricalAwards=false
• 关键词: Regulation; Axonal; Neurofilament; Dynamics; Phosphorylation

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.

神经元是大脑中让我们思考、感觉和移动的细胞，它有一种非常独特的形状，被称为“极化”。从神经元的一侧延伸出来的是许多手指状的延伸（“树突”），它们接收来自其他神经元的信息，从另一侧延伸出来的是一个更长的延伸（“轴突”），它将这些信息的总和传递给下一个神经元。神经元是如何形成这种独特的极化形式，并在个体的一生中保持这种形式的，目前还不完全清楚。然而，它至少部分地依赖于被称为“细胞骨架”的蛋白质纤维网络。这个网络为神经元形成了一种骨架，帮助神经元保持其形状。然而，与骨骼不同的是，细胞骨架的部分是不断被替换的。这给神经元带来了困难的局面，因为所有的蛋白质都是在细胞体中合成的，然后必须通过一个称为“轴突运输”的过程组装并运输到轴突内并沿着轴突运输。这个过程必须受到高度调控，否则蛋白质就会不正确地组装，或者在轴突的开始处聚集，神经元就可能死亡。在一些神经元中，轴突运输必须进行长距离。例如，坐骨神经，沿着我们的腿一直延伸，它所有的细胞骨架蛋白都来自脊柱附近的一个小细胞体。我们的研究考察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。神经元有一组修饰酶，称为“激酶”，可以可逆地修饰神经丝。对于这种修改，一个简单的类比是给笔戴上笔帽。当笔被盖上时，它的书写功能就改变了。当盖子被取下时，它的功能恢复了。而不是每次我们需要写的时候都合成一支新的笔，而是在再次需要它的时候给笔盖上盖子。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轴突运输转变为与其他神经丝相互作用，形成支持轴突的强束。利用基因工程激酶和神经丝蛋白，我们将监测这些变化。这些研究将提供轴突运输和稳定的重要信息。