Milton and the Transport of Mitochondria

描述（由申请人提供）：马达蛋白在细胞质内移动细胞器，从而有助于这些细胞器的适当分布。从细胞生物学的观点来看，所涉及的马达，包括驱动蛋白家族的成员，是相当有趣的：马达是如何与它们的适当的货物结合的？他们如何将这些货物运送到特定的地点？他们的活动是如何管理的？细胞器的正确分布是如何实现和维持的？细胞器的正确分布可能会给细胞带来复杂的问题。这一过程的缺陷可导致周围神经病变，并与一些神经退行性疾病有关。线粒体是高度移动的细胞器。它们必须在细胞内分布，以便能够为细胞的每个部分提供足够的能量，以满足该部分的需求。线粒体在神经元轴突和树突上的上下运动是线粒体运输的最引人注目的例子之一。在一种叫做米尔顿的果蝇突变体中，神经轴突和末端完全没有线粒体。 米尔顿基因编码的蛋白质存在于线粒体中，与运动蛋白驱动蛋白相关。目前的建议旨在了解米尔顿在神经元和其他细胞内的线粒体运输中的作用。第一个目标，主要涉及荧光和视频显微镜，旨在确定什么形式的运输需要米尔顿，并确定是否米尔顿是对所有线粒体或只有那些正在进行运输。随后的目标是探索米尔顿行动的机制，主要是通过生物化学研究。他们询问了米尔顿是如何定位于线粒体的，米尔顿是如何与驱动蛋白相互作用的，以及米尔顿是否充当了连接驱动蛋白和线粒体的适配器。在此过程中，该提案还审查了米尔顿基因的选择性剪接和米尔顿的翻译后修饰的潜在调控作用。

DESCRIPTION (provided by applicant): Motor proteins move organelles within the cytoplasm of cells and thereby contribute to the appropriate distribution of those organelles. The motors involved, including members of the kinesin family, are of considerable interest from the cell biological point of view: how do motors couple to their appropriate cargos?; how do they direct those cargos to particular locations?; how is their activity regulated?; how is the proper distribution of the organelle achieved and maintained? The proper distribution of an organelle can pose a complex problem for a cell. Defects in this process can cause peripheral neuropathies and have been implicated in some neurodegenerative diseases. Mitochondria are highly mobile organelles. They must distribute themselves within cells so as to be able to supply sufficient energy to each part of a cell to match the needs of that part. The movement of mitochondria up and down axons and dendrites of neurons is one of the most dramatic examples of mitochondrial transport. In a Drosophila mutant called milton, mitochondria are completely absent from nerve axons and terminals. The protein encoded by the milton gene is found on mitochondria and is associated with the motor protein kinesin. The present proposal seeks to understand the role of Milton in the transport of mitchondria within neurons and other cells. The first aim, involving primarily fluorescent and video microscopy, seeks to determine what forms of transport require Milton and to determine if Milton is on all mitochondria or only those that are undergoing transport. The subsequent aims probe the mechanism of Milton action, primarily through biochemical studies. They inquire how Milton is localized to mitochondria, how Milton interacts with kinesin, and whether Milton serves as an adaptor that links kinesin to the mitochondrion. In the process, the proposal also examines the alternative splicing of the Milton gene and the potential regulatory role of post-translational modifications of Milton.