CAUSES AND CONSEQUENCES OF ALPHA-SYNUCLEIN AGGREGATION
α-突触核蛋白聚集的原因和后果
基本信息
- 批准号:7431633
- 负责人:
- 金额:$ 54.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-06-01 至 2008-05-31
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAcetylcysteineAlpha-Synuclein transgenic mouseAlzheimer&aposs DiseaseAmino AcidsAmyloidAmyloid beta-ProteinAmyloid beta-Protein PrecursorAnimal ModelAntioxidantsBehavioralBiochemicalBiological AssayBromidesCell LineCellsCellular AssayComplementDevelopmentEaglesElectron MicroscopyEnzyme-Linked Immunosorbent AssayExtravasationGlial Fibrillary Acidic ProteinGonadotropin Hormone Releasing HormoneGonadotropinsGrowth Associated Protein 43HumanImmunoblottingIn VitroLDL-Receptor Related Protein 1LDL-Receptor Related ProteinsLabelLactoseLaser Scanning Confocal MicroscopyLewy BodiesLewy Body DiseaseLightLow Density Lipoprotein ReceptorMarinesMotorMusMutationNeuronsOxidative StressOxidoreductaseParkinson DiseaseParkinsonian DisordersPathogenesisPatientsPeptidesPhosphate BufferPlatelet-Derived Growth FactorPlayPolyacrylamide Gel ElectrophoresisPolymerase Chain ReactionPresenile Alzheimer DementiaProteinsPurposeResearch PersonnelRoleSOD2 geneSalineSodium Dodecyl Sulfate-PAGESuperoxide DismutaseTestingTetrazoliumTherapeuticTransgenic MiceTransgenic OrganismsTyrosine 3-MonooxygenaseVitamin Ealpha synucleinamyloid peptidecatalasediphenylearly onsetfamilial Alzheimer diseasehydroxypropyl methacrylatelucifer yellowmotor deficitmouse modelmutantneurochemistryoxidationpeptide Apreventprogramspromoterprotein expressionreceptorresearch studysuperoxide dismutase 1synucleinsynuclein, alpha (non A4 component of amyloid precursor) protein, humanuptake
项目摘要
Parkinson's disease (PD) and related Lewy body diseases are associated with the abnormal intraneuronal accumulation of alpha-synuclein. Mutations that enhance the propensity of alpha-synuclein to aggregate cause early onset familial PD. Notably, the majority of patients with Alzheimer's disease (AD) also have alpha-synuclein immunoreactive Lewy bodies and a substantial proportion of them develop a form of parkinsonism that defies conventional therapeutic approaches. This suggests that factors involved in the pathogenesis of AD might promote the development of particularly recalcitrant forms of PD. We have shown that amyloid beta peptides (Abeta), which play a central role in AD pathogenesis, promote the intracellular accumulation of alpha-synuclein and accelerate alpha-synuclein-dependent motor deficits in alpha-synuclein/amyloid precursor protein transgenic mice, an animal model that mimics aspects of Lewy body disease. However, the mechanisms underlying these effects remain unknown. The main objectives of this proposal are to elucidate these mechanisms and to determine whether blocking Abeta effects might prevent or ameliorate PD and other Lewy body diseases. In Aim 1 we will determine whether the increase in neuronal alpha-synuclein accumulation and in alpha-synuclein-dependent deficits in a transgenic mouse model of Lewy body disease depends on the ratio of the two predominant Abeta species (Abeta1-42/Abeta1-40). For this purpose, alpha-synuclein transgenic mice will be crossed with wildtype or mutant human amyloid precursor protein (hAPP) transgenic mice and detailed biochemical, neuropathological and behavioral analysis will be performed. These experiments will be complemented with in vitro studies in alpha-synuclein-transfected cell fines treated with Abeta1-42 or Abeta1-40 or a mixture of both. In Aim 2 we will determine whether the increase in neuronal alpha-synuclein
accumulation and in alpha-synuclein-dependent deficits in a transgenic mouse model of Lewy body disease depends on the uptake of secreted Abeta via the LDL receptor-related protein (LRP). For this purpose, mice expressing both alpha-synuclein and wildtype or mutant hAPP will be crossed with receptor associated protein-deficient mice, which have reduced LRP expression. These experiments will be complemented with in vitro studies in alpha-synuclein-transfected cell lines. In Aim 3 we will determine whether Abeta-dependent alpha-synuclein aggregation and alpha-synuclein-dependent neuronal deficits can be reduced by antioxidants. For this purpose, alpha-synuclein/hAPP mice will be crossed with superoxide dismutase 1 or 2 transgenic mice. These experiments will be complemented with in vitro studies in synuclein-transfected cell lines treated with antioxidants. These experiments will shed light on the overlap between AD and PD and on the role of hAPP/Abeta in the pathogenesis of PD and other Lewy body diseases.
帕金森病(PD)和相关的路易体疾病与α-突触核蛋白在神经元内的异常积聚有关。增加α-突触核蛋白聚集倾向的突变会导致早发性家族性帕金森病。值得注意的是,大多数阿尔茨海默病(AD)患者也有α-突触核蛋白免疫反应的路易小体,其中相当一部分人患上了一种违反传统治疗方法的帕金森病。这表明参与AD发病机制的因素可能促进特别顽固性PD的发展。我们已经证明,在AD发病机制中发挥核心作用的淀粉样β多肽(Abeta)可以促进α-突触核蛋白在细胞内的积累,并加速α-突触核蛋白依赖的运动缺陷,这是一种模拟路易体疾病的动物模型。然而,这些效应背后的机制仍不清楚。这项建议的主要目的是阐明这些机制,并确定阻断Abeta效应是否可以预防或改善帕金森病和其他路易体疾病。在目标1中,我们将确定在路易体病转基因小鼠模型中,神经元α-突触核蛋白积累和α-突触核蛋白依赖缺陷的增加是否取决于两个主要Abeta物种(Abeta1-42/Abeta1-40)的比率。为此,将α-突触核蛋白转基因小鼠与野生型或突变型人淀粉样前体蛋白(HAPP)转基因小鼠杂交,并进行详细的生化、神经病理和行为分析。这些实验将与用Abeta1-42或Abeta1-40或两者的混合物处理的α-突触核蛋白转基因细胞的体外研究相补充。在目标2中,我们将确定神经元α-突触核蛋白的增加
路易体病转基因小鼠模型的蓄积和α-突触核蛋白依赖缺陷取决于通过低密度脂蛋白受体相关蛋白(LRP)对分泌的Abeta的摄取。为此,同时表达α-突触核蛋白和野生型或突变型HAPP的小鼠将与受体相关蛋白缺陷小鼠杂交,后者降低了LRP的表达。这些实验将与α-突触核蛋白转基因细胞系的体外研究相辅相成。在目标3中,我们将确定抗氧化剂是否可以减少α-突触核蛋白聚集和α-突触核蛋白依赖的神经元缺陷。为此,α-突触核蛋白/HAPP小鼠将与超氧化物歧化酶1或2转基因小鼠杂交。这些实验将与体外研究相补充,在体外研究中使用抗氧化剂处理过的突触核蛋白转基因细胞系。这些实验将阐明AD和PD之间的重叠以及HAPP/Aβ在PD和其他路易体疾病发病机制中的作用。
项目成果
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ELIEZER MASLIAH其他文献
ELIEZER MASLIAH的其他文献
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{{ truncateString('ELIEZER MASLIAH', 18)}}的其他基金
Clearance Pathways in the CNS in Aging and HIV
衰老和艾滋病毒中枢神经系统的清除途径
- 批准号:
8463090 - 财政年份:2012
- 资助金额:
$ 54.91万 - 项目类别:
Clearance Pathways in the CNS in Aging and HIV
衰老和艾滋病毒中枢神经系统的清除途径
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Clearance Pathways in the CNS in Aging and HIV
衰老和艾滋病毒中枢神经系统的清除途径
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MULTI-DISCIPLINARY APPROACHES FOR PRECLINICAL RESEARCH IN PARKINSONS DISEASE
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7957613 - 财政年份:2009
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MULTI-DISCIPLINARY APPROACHES FOR PRECLINICAL RESEARCH IN PARKINSONS DISEASE
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