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.

神经元的形状比其他任何细胞都要更长更复杂，因此它们面临着 更大的挑战是在整个乔木中分布和维持线粒体。 神经元可以持续一生，但蛋白质转换得很快。因此，线粒体需要 无论它们离索马有多远， 大多数线粒体蛋白质的基因所在的地方。线粒体从索马体到 边缘可能是恢复边缘人口的一种手段，但越来越多的证据表明， 表明轴突和树突中的局部蛋白质合成也可能为线粒体提供 需求这对于半衰期很短的蛋白质可能尤其如此; 不太可能在轴突的长途旅行中幸存下来。一种这样的蛋白质是PINK 1，其半衰期为 估计只有几分钟的时间PINK 1的持续合成和降解是 PINK 1在线粒体质量控制中的功能的当前模型的基本特征。 与这个模型相一致，我们发现选择性地阻断轴突中的蛋白质合成， 阻止PINK 1/Parkin通路的局部激活， 富含轴突目前的建议是根据这些调查结果和观察结果提出的， PINK 1 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）存在一种机制， 定位PINK 1 mRNA，以及可能的许多其他线粒体蛋白质转录物， PINK 1的mRNA被转运到轴突中， 树突凭借其与线粒体的协会。因此，我们建议确定 PINK 1转录物中与线粒体结合所需的序列， 以确定介导这种关联的蛋白质因子，并确定这种关联是否是 轴突中转录本的存在和PINK 1的局部诱导所需的 依赖性线粒体自噬我们亦建议决定是否有类似的机制运作 对于其他蛋白质，并且是保持线粒体和轴突健康所必需的。因为 线粒体运输和线粒体自噬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持 线粒体健康在一个巨大的乔木和是否线粒体上的mRNA的运输是一部分 这个机制。