The COPA vesicle protein and pathogenesis of spinal muscular atrophy

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 表明病理低水平的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， 这些实验应该会对这些疾病中发生的异常过程产生新的见解。 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。

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.