Axonal Transport of mRNA for Mitochondrial Proteins

线粒体蛋白 mRNA 的轴突运输

• 批准号: 9921501
• 负责人: Thomas L. Schwarz
• 金额: $ 44.59万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921501
• 关键词: Address; Axon; Axonal Transport; Brain; Cell Nucleus; Cells; Cis-Acting Sequence; Complex; Data; Defect; Dendrites; Distal; Distant; Elements; Face; Genes; Half-Life; Health; Hippocampus (Brain); Hour; Human; Location; Mediating; Messenger RNA; Mitochondria; Mitochondrial Proteins; Modeling; Motor; Mutate; Neurodegenerative Disorders; Neurons; PINK1 gene; PTEN-induced putative kinase; Parkinson Disease; Pathway interactions; Peripheral; Population; Protein Biosynthesis; Proteins; Quality Control; Rejuvenation; Sensory; Shapes; Site; Surface; Trans-Activators; Transcript; Translations; base; in vivo; meter; mitochondrial messenger RNA; neuronal cell body; parkin gene/protein; preservation; prevent; protein degradation; protein function; protein transport; tissue culture

Neurons have more extended and complex shapes than any other cell and consequently face a far greater challenge in distributing and maintaining mitochondria throughout their arbors. Neurons can last a lifetime, but proteins turn over rapidly. Mitochondria, therefore, need constant rejuvenation of their protein components no matter how far they are from the soma where the genes for most mitochondrial proteins reside. Transport of mitochondria from soma to periphery may be one means of rejuvenating the peripheral population, but mounting evidence indicates that local protein synthesis in axons and dendrites may also supply mitochondrial needs. This may be particularly true for proteins with very short half-lives; proteins that would be unlikely to survive the long trip down an axon. One such protein is PINK1, whose half-life is estimated to be on the order of a few minutes. Constant synthesis and degradation of PINK1 is an essential feature of current models for PINK1 function in mitochondrial quality control. Consistent with this model, we have found that blocking proteins synthesis selectively in axons prevents the local activation of the PINK1/Parkin pathway for mitophagy and that PINK1 mRNA is enriched in axons. The current proposal is based on these findings and also the observation that PINK1 mRNA colocalizes with mitochondria in axons and dendrites and is present on moving mitochondria. We have therefore hypothesized 1) the existence of a mechanism to localize PINK1 mRNA, and potentially many other transcripts for mitochondrial proteins, to the surface of the mitochondrion and 2) that mRNA for PINK1 is transported into axons and dendrites by virtue of its association with mitochondria. We have therefore proposed to identify the sequences within the PINK1 transcript that are required for its association with mitochondria, to identify the protein factors that mediate that association, and to determine if the association is required for the presence of the transcript in axons and for the local induction of PINK1- dependent mitophagy. We further propose to determine whether a similar mechanism operates for other proteins and is necessary for preserving mitochondrial and axonal health. Because defects in mitochondrial transport and mitophagy are implicated in Parkinson's and other neurodegenerative disorders, it is necessary to understand how a neuron can preserve mitochondrial health in a vast arbor and whether the transport of mRNA on mitochondria is part of that mechanism.

神经元比任何其他细胞都具有更延长和复杂的形状，因此面对 在整个乔木中分发和维持线粒体方面的挑战要大得多。 神经元可以持续一生，但蛋白质迅速翻转。因此，线粒体需要 无论距离Soma多远，它们的蛋白质成分不断恢复活力 大多数线粒体蛋白的基因都存在。线粒体从SOMA运输到 外围可能是使外围人口恢复活力的一种手段，但越来越多的证据 表明轴突和树突中的局部蛋白质合成也可能提供线粒体 需要。对于半衰期很短的蛋白质，可能尤其如此。蛋白质会 不可能在轴突沿着长途旅行中生存。一种这样的蛋白质是pink1，其半衰期是 估计为几分钟的顺序。 pink1的恒定合成和降解为 线粒体质量控制中PINK1功能的当前模型的一个基本特征。 与该模型一致，我们发现在轴突中选择性地阻断蛋白质合成 防止pink1/parkin途径的局部激活线粒体和那个pink1 mRNA 富含轴突。当前的建议基于这些发现，也基于观察结果 那个粉红色的mRNA与轴突和树突中的线粒体共定位，并存在于 移动线粒体。因此，我们假设1）存在机制 将pink1 mRNA定位于线粒体蛋白，可能是许多其他成绩单 线粒体的表面和2）pink1的mRNA被转运到轴突和 树突依赖于线粒体的关联。因此，我们建议确定 与线粒体相关的pink1转录本中的序列， 确定介导该关联的蛋白质因子，并确定关联是否为 在轴突中存在转录本和pink1-局部诱导所必需的 依赖的线粒体。我们进一步建议确定类似机制是否运行 对于其他蛋白质，对于保持线粒体和轴突健康是必不可少的。因为 线粒体运输和线粒体的缺陷与帕金森氏症和其他 神经退行性疾病，有必要了解神经元如何保存 线粒体健康在广阔的乔木中以及mRNA在线粒体上的运输是否是一部分 该机制。