Axonal Transport of mRNA for Mitochondrial Proteins

线粒体蛋白 mRNA 的轴突运输

• 批准号: 10430133
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430133
• 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; Parkin; 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; 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广泛和更复杂的形状，因此面临着 在其乔木中分布和维护线粒体的挑战要大得多。 神经元可以持续一生，但蛋白质会迅速翻转。因此，线粒体需要 无论它们离胞体有多远，它们的蛋白质成分都会不断恢复活力 大多数线粒体蛋白质的基因都在那里。线粒体从胞体到胞体的运输 边缘可能是振兴边缘人群的一种手段，但越来越多的证据表明 提示轴突和树突中的局部蛋白质合成也可能为线粒体提供 需要。对于半衰期很短的蛋白质来说可能尤其如此；这种蛋白质将 不太可能在沿着轴突的长途旅行中存活下来。一种这样的蛋白质是PINK1，它的半衰期是 估计在几分钟左右。PINK1 IS的持续合成和降解 当前PINK1功能模型在线粒体质量控制中的一个基本特征。 与这个模型一致，我们发现在轴突中选择性地阻止蛋白质的合成。 阻止局部激活PINK1/Parkin通路进行有丝分裂和PINK1 mRNA 富含轴突。目前的建议是基于这些发现和观察所得 PINK1mRNA与线粒体共存于轴突和树突中，并存在于 移动线粒体。因此，我们假设1)存在一种机制来 将PINK1 mRNA和潜在的许多其他线粒体蛋白转录本定位到 2)PINK1的mRNA被运输到轴突和 树突由于其与线粒体的联系。因此，我们建议确定 PINK1转录本内与线粒体结合所需的序列， 确定调节这种联系的蛋白质因素，并确定这种联系是否 转录本在轴突中的存在和PINK1的局部诱导- 依赖有丝分裂。我们进一步建议确定是否有类似的机制运作。 对于其他蛋白质来说，这是保护线粒体和轴突健康所必需的。因为 线粒体转运和吞丝分裂缺陷与帕金森病和其他疾病有关 神经退行性疾病，有必要了解神经元如何保存 巨大乔木中线粒体的健康状况以及线粒体上的mRNA运输是否是一部分 这一机制。