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The COPA vesicle protein and pathogenesis of spinal muscular atrophy

COPA囊泡蛋白与脊髓性肌萎缩症发病机制

基本信息

批准号：
10612848
负责人：
ELLIOT J. ANDROPHY
金额：
$ 38.22万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612848
关键词：
3&apos Untranslated Regions Affect Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Applications Grants Axon Axonal Transport Binding Binding Proteins Biochemical Biological CRISPR/Cas technology Carrier Proteins Cells Co-Immunoprecipitations Coat Protein Complex I Complex Coupled Data Defect Dependence Development Disease Endoplasmic Reticulum Etiology Formaldehyde Functional disorder G-Protein-Coupled Receptors Genes Genetic Golgi Apparatus Grant High-Throughput RNA Sequencing Immunoprecipitation In Vitro Infant Mortality Intracellular Transport Investigation Learning Link Lipids Longevity Maintenance Messenger RNA MicroRNAs Modeling Molecular Morphology Motor Motor Neurons Movement Mus Muscle Muscle Weakness Mutation Myopathy Nerve Nerve Degeneration Neurites Neurodegenerative Disorders Neuromuscular Junction Neuronal Dysfunction Neurons Nucleic Acids Outcome Pathogenesis Pathologic Pathway interactions Peptide Signal Sequences Process Property Proteins Proteomics Publishing RNA RNA-Binding Proteins Reporting Role SMN protein (spinal muscular atrophy)Series Spinal Muscular Atrophy System Techniques Test Result Testing Tissues Transgenic Mice Transgenic Organisms Transmembrane Transport Vesicle Western Blotting coping crosslink embryonic stem cell exosome experimental study extracellular vesicles in vivo insight motor neuron function mouse model mutant neuronal cell body novel overexpression pharmacologic receptor binding trafficking

项目摘要

ABSTRACT The pathogenesis of motor neuron and muscle dysfunction in spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, is still unresolved. SMA results from low levels of the Survival Motor Neuron SMN protein. The rationale underlying these experiments is our discovery that the SMN protein binds to and moves in neurons together with the CopA protein, the largest constituent of the heptameric COPI coatomer complex. The objective of this proposal is to determine the molecular mechanisms by which reduced SMN interaction with COPI complex and loss of COPI activities leads to neurodegeneration. Golgi-derived COPI vesicles are necessary for post-translational processing and transport of proteins and other cargoes between Golgi apparatus and endoplasmic reticulum and secretory pathway. Golgi alterations have been observed in SMA, amyotrophic lateral sclerosis, Alzheimer’s disease, and other neurodegenerative disorders. Our data demonstrate that pathologically low levels of SMN alter the morphology and functionality of the Golgi apparatus. The overall premise of this proposal is that the COPI complex is necessary for processing and trafficking of cargoes essential for normal motor neuron maintenance. We have also shown that specific mRNAs are found in association with COPI. One class of cargo emphasized in this grant is mRNA selected for axonal transport. We propose genetic, biochemical, proteomic and transgenic approaches to define the properties and activities of the COPI complex and its interactions with SMN and other potential binding partners. We will create murine models to investigate the role of COPI in the neuron and perform correlative in vivo studies of axonogenesis, RNA trafficking and pathologic biological outcomes. Because SMN physically interacts with factors linked to other neurodegenerative diseases, thereby implicating commonality of causality, these experiments should result in new insights into the aberrant processes occurring in these disorders. Moreover, pharmacologic induction of the COPI pathway may represent a novel objective for treatment of SMA and other neurodegenerative diseases.

摘要脊髓性肌萎缩症（SMA）是一种主要的遗传性疾病，婴儿死亡的原因仍然没有得到解决。SMA由低水平的运动神经元生存SMN引起蛋白这些实验的基本原理是我们发现SMN蛋白结合并移动在神经元中与CopA蛋白一起，CopA蛋白是七聚体COPI外被体复合物的最大成分。本提案的目的是确定减少SMN相互作用的分子机制与COPI复合物和COPI活性的丧失导致神经变性。高尔基体衍生的COPI囊泡是蛋白质和其他货物在高尔基体之间的翻译后加工和运输所必需的内质网和分泌途径。在SMA中观察到高尔基体改变，肌萎缩侧索硬化症、阿尔茨海默病和其他神经退行性疾病。我们的数据证明病理性低水平的SMN改变了高尔基体的形态和功能设备.本提案的总体前提是，COPI复合体对于处理和运输对正常运动神经元维持必不可少的货物。我们还表明，发现mRNA与COPI相关。在这项资助中强调的一类货物是mRNA，轴突运输我们提出了遗传学、生物化学、蛋白质组学和转基因的方法来定义 COPI复合物的性质和活性及其与SMN和其他潜在结合的相互作用伙伴我们将建立小鼠模型来研究COPI在神经元中的作用，并进行相关的研究。轴突发生、RNA运输和病理生物学结果的体内研究。因为SMN在物理上与其他神经退行性疾病相关因素相互作用，从而暗示因果关系的共性，这些实验应该导致对这些疾病中发生的异常过程的新的认识。此外，COPI通路的药物诱导可能代表SMA治疗的新目标和其他神经退行性疾病。