Self-association and membrane binding of alpha-synuclein

α-突触核蛋白的自缔合和膜结合

• 批准号: 9066445
• 负责人: Elizabeth Rhoades
• 金额: $ 32.96万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066445
• 关键词: Acidic Region; Affect; Binding; C-terminal; Cartoons; Cell Death; Cells; Cellular Membrane; Cereals; Characteristics; Complex; Complication; Consensus; Defect; Deposition; Development; Disease; Dopaminergic Cell; Drosophila genus; Energy Transfer; Environment; Fluorescence; Fluorescence Resonance Energy Transfer; Functional disorder; Genes; Goals; Health; Investigation; Label; Lewy Bodies; Life; Link; Lipid Bilayers; Lipids; Measurement; Measures; Membrane; Methods; Modeling; Molecular; Molecular Target; Motor; Movement Disorders; Mutation; N-terminal; Nerve Degeneration; Neurons; Parkinson Disease; Pathology; Point Mutation; Population; Positioning Attribute; Process; Property; Proteins; Publications; Research; Rodent; Role; Signal Transduction; Solutions; Spectrum Analysis; Structure; Synaptic Vesicles; Time; Toxic effect; Transgenic Organisms; Work; aged; alpha synuclein; insight; membrane model; monomer; mutant; novel; overexpression; prevent; protein aggregate; research study; single molecule; synuclein; therapeutic development

DESCRIPTION (provided by applicant): Parkinson's disease is the most common neurodegenerative movement disorder, affecting an estimated 1% of the population aged 65 and older. The protein �-synuclein is the primary component of Lewy bodies, the neuronal cytoplasmic deposits of aggregated proteins that are the hallmark of Parkinson's disease. There is compelling evidence that the process of �-synuclein aggregation is directly related to Parkinson's disease pathology. However, the aggregation of �-synuclein is a complex, heterogeneous process during which multiple oligomeric protein species are populated at various timepoints and persist over a range of timescales, making its complete characterization extremely challenging. Moreover, the relationship between the various molecular species formed in the aggregation process and disease pathology is still an open question, although the direct interaction between oligomeric �-synuclein and cellular membranes has been implicated. An additional complication comes from two recent publications that provide evidence that the native state of �- synuclein, long believed to be a disordered monomer, may actually be a partially structured tetramer. Our hypothesis is that both the functional and dysfunctional interactions of AS are modulated by changes in the average conformational or oligomeric ensemble and the dynamic interchange between states within these ensembles. Our research will characterize these ensembles in solution (Aim 1), bound to model membranes (Aim 2), and in living cells (Aim 3), with the goal of determining physical features that are associated with th transition to toxic states. As a consequence of these experiments, we will also determine the relationship between the putative tetramer and monomer forms of AS. To do this, we will use single molecule and time- resolved fluorescence methods. Our experimental approaches have the advantage of allowing for the characterization of �-synuclein under conditions that favor oligomerization or aggregation without the complication of signal interpretation that accompanies actual self-association of the protein. The results of our investigation will be a comprehensive view of what properties of the solution, membrane, and cellular environment favor self-association of �-synuclein into toxic structures. Such understanding is critical to the long term goal of our research group to identify potential molecular targets for the development of therapeutics to treat or prevent Parkinson's disease.

描述（申请人证明）：帕金森氏病是最常见的神经退行性运动障碍，影响和估计为65岁及以上的1％ULATION蛋白质。帕金森氏病都有令人信服在各种分子物种中，形成的IND疾病病理学的关系仍然是一个开放的问题，寡聚蛋白和细胞膜之间的相互作用已被涉及f synnuclein。我们的假设是，我们的假设是平均供应或橄榄型合奏的功能和功能障碍的相互作用，以及在这些乐器中S之间的动态互换AIM 2），在活细胞中（AIM 3），确定与有毒状态的物理学的目标我们的分子和时间分辨率的荧光方法是否会均匀地塑造或同意，而没有信号解释的并发症。这种理解对于我们的研究小组的长期目标至关重要，即确定用于发展或预防帕金森氏病的疗法的潜在分子靶标。