Genome Wide Analysis of Alpha-Synuclein Neurotoxicity

α-突触核蛋白神经毒性的全基因组分析

基本信息

批准号：
9272475
负责人：
MEL B FEANY
金额：
$ 61.07万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272475
关键词：
Address Animal Model Biochemical Biological Biological Models Cells Clinical Cytoplasmic Inclusion Data Defect Deposition Diffuse Disease Drosophila genus Equipment and supply inventories Functional disorder Gene Dosage Genes Genetic Genetic Models Genetic Screening Genomics Human Impairment Lewy Bodies Lewy Body Dementia Mediating Modeling Modification Molecular Movement Disorders Multiple System Atrophy Nerve Degeneration Neurites Neurodegenerative Disorders Neuroglia Neurologist Neurons Parkinson Disease Parkinson&apos s Dementia Pathogenesis Pathologic Pathology Pathway interactions Patients Physiological Point Mutation Population Process Proteins Somatotype Synapses System Testing Time Toxic effect alpha synuclein alpha synuclein gene base cell type clinically significant design dopaminergic neuron early onset experimental study gene product genetic analysis genetic approach genome wide association study genome-wide genome-wide analysis in vivo insight nervous system disorder neuropathology neurotoxicity non-motor symptom novel protein aggregate synucleinopathy therapeutic target

项目摘要

Parkinson's disease is the most common neurodegenerative movement disorder and is characterized pathologically by the intraneuronal deposition of abnormally phosphorylated and aggregated α-synuclein protein. Abnormal deposition of α-synuclein into neuronal and glial aggregates is also the primary pathologic feature of a group of collectively even more common disorders, termed the α-synucleinopathies. To define the molecular mechanisms controlling α-synuclein induced neurodegeneration we and others have modeled α-synucleinopathies in the simple and powerful genetic model organism Drosophila. Genetic, biochemical and cell biological experiments in Drosophila have provided important clues regarding the pathogenesis of α-synucleinopathies. However, the unbiased forward genetic screens providing the bases for these studies, while valuable, have to date remained incomplete. Here we propose to use a newly created and powerful Drosophila model of α-synucleinopathies to perform a comprehensive genetic analysis of α-synuclein neurotoxicity in vivo. These studies will for the first time provide a broad analysis of mechanisms controlling α-synuclein toxicity to postmitotic neurons and should identify many new high-value therapeutic targets. Our studies will be particularly important as more and more data emerges from genome wide associated studies showing genetic influences on Parkinson's disease and related α-synucleinopathies, but with little clear evidence as to the mechanism of action of these newly identified gene products in neurodegenerative disease pathogenesis.

帕金森病是最常见的神经退行性运动障碍，其特征是病理学上是由于异常磷酸化和聚集的 α-突触核蛋白在神经元内沉积 α-突触核蛋白异常沉积到神经元和神经胶质聚集体也是主要的病理原因。一组更常见的疾病的特征，称为 α-突触核蛋白病。我们和其他人模拟了控制 α-突触核蛋白诱导的神经变性的分子机制简单而强大的遗传模型生物果蝇中的 α-突触核蛋白病遗传、生化。果蝇的细胞生物学实验为了解该病的发病机制提供了重要线索。然而，无偏见的正向遗传筛选为这些研究提供了基础，虽然有价值，但迄今为止仍然不完整，在这里我们建议使用新创建的强大的。 α-突触核蛋白病果蝇模型对 α-突触核蛋白进行全面的遗传分析这些研究将首次对控制机制进行广泛的分析。 α-突触核蛋白对有丝分裂后神经元的毒性，应该确定许多新的高价值治疗靶点。随着越来越多的数据来自全基因组相关的数据，我们的研究将变得尤为重要研究表明遗传对帕金森病和相关 α-突触核蛋白病有影响，但几乎没有研究这些新发现的基因产物在神经退行性疾病中的作用机制有明确的证据疾病发病机制。