MSA 转基因模型中的 a-突触核蛋白-猫眼课题宝

MSA 转基因模型中的 a-突触核蛋白

批准号：

8539081

负责人：

ELIEZER MASLIAH

金额：

$33.24万

依托单位：

MAYO CLINIC ROCHESTER

依托单位国家：

美国

项目类别：

财政年份：

2003

资助国家：

美国

项目状态：

未结题

起止时间：

2003-09-30 至

来源：

https://reporter.nih.gov/project-details/8539081

关键词：

3-nitropropionic acid ADRBK1 gene Age-Months Aging-Related Process Antioxidants Ataxia Autonomic Dysfunction Behavioral Brain Calcium Cell Count Cells Cerebrum Collaborations Complement Confocal Microscopy Cytoplasmic Inclusion Dementia Diagnosis Disease Dose Dysautonomias Electron Microscopy Flavonoids Functional disorder Funding G protein coupled receptor kinase GRK5 gene Generations Human Immunoblotting Impairment In Vitro Infection Injection of therapeutic agent Integrins Knockout Mice Lewy Body Dementia Light Link Mediating Mediator of activation protein Methods Mitochondria Modeling Modification Multiple System Atrophy Mus Mutate Myelin Myelin Basic Proteins Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neuroglia Neurons Oligodendroglia Oxidative Phosphorylation Oxidative Stress Parkinsonian Disorders Pathogenesis Pathway interactions Pattern Performance Phosphorylation Play Prevention strategy Process Proteins Receptor Signaling Resistance Rifampin Role Subfamily lentivirinae Synapses Testing Therapeutic Therapeutic Uses Time Toxic effect Toxin Transgenic Mice Transgenic Model Wild Type Mouse alpha synuclein caspase-3 immunocytochemistry in vivo in vivo Model mitochondrial dysfunction mouse myelin basic protein mutant nerve stem cell nervous system disorder neurotoxic neurotoxicity novel therapeutics prevent promoter protein misfolding research study response synuclein

中文摘要

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英文摘要

Multiple system atrophy (MSA) is a progressive, degenerative neurological disorder characterized by parkinsonism, ataxia & dysautonomia. The cardinal pathological feature of MSA is the presence of glial cytoplasmic inclusions composed of alpha-synuclein (SYN) in oligodendrocytes. Recent studies suggest that abnormal SYN accumulation in neurons & glia leads to cellular dysfunction & neurodegeneration. During the previous funding period we developed in vitro & in vivo models of MSA showing that mitochondrial damage & hyperphosphorylated SYN aggregate generation may contribute to the pathogensis of MSA. However, mechanisms by which these pathways promote oligodendrogial dysfunction & neurodegeneration are unclear. In this renewal we will investigate the role of mitochondrial dysfunction in SYN phosphorylation & toxicity. Our central hypothesis is that oxidative stress due to mitochondrial dysfuntion may promote G-protein coupled receptor kinase (GRK) activation & toxic SYN phosphorylation. The main objective is to investigate neurodegeneration in MSA-like SYN transgenic (tg) models to determine if reducing SYN accumulation represents a therapeutic strategy for MSA. Aim 1. In order to determine the role of hyperphosphorylated SYN accumulation in oligodendrocj^es in the mechanisms of neurotoxicity, we will analyze SYN accumulation & neurodegeneration in myelin basic protein (MBP)-SYN tg mice expressing wild-type (wt) human SYN or a nonphosphorylatable SYN mutant (S129A). MBP-SYNwt tg mice will be crossed with GRK2- or GRKS-deficient mice & MBP-SYNwt tg mice & MBP-SYN(S129A) tg mice will receive intra-cerebral infections with lentivirus expressing GRK2 or GRK5 under a oligodendroglial specific promoter (MBP). Aim 2. In order to determine the role of mitochondrial dysfunction & oxidative stress on GRK activation & SYN phosphorylation, MBP-SYN (wt and S129A) mice & oligodendroglial cells will be challenged with 3- nitropropionic acid. Aim 3. In order to determine if neuronal impairments in MSA models can be ameliorated by reducing SYN aggregation or inhibiting GRKs, MBP-SYN wt tg mice will be treated with rifampicin or GRK blockers. Behavioral performance, neurodegeneration, SYN oligomerization & phosphorylation & GRK activity will be assessed

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