COPA囊泡蛋白与脊髓性肌萎缩症发病机制-猫眼课题宝

COPA囊泡蛋白与脊髓性肌萎缩症发病机制

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

项目状态：

未结题

起止时间：

2013-08-15 至 2025-04-30

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

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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.

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