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.

神经元的形状比任何其他细胞都要延伸和复杂，因此面临着一个复杂的环境