Alpha Synuclein, cellular dysfunction and Parkinson disease

α 突触核蛋白、细胞功能障碍和帕金森病

• 批准号: 8552517
• 负责人: Mark Cookson
• 金额: $ 17.49万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552517
• 关键词: Animal Model; Biological Models; Brain; Cell Line; Cell model; Cells; Characteristics; Cultured Cells; Data; Dementia; Deposition; Disease; Event; Functional disorder; Genes; Goals; Incidence; Lewy Bodies; Molecular; Mutation; Neurons; Parkinson Disease; Process; Proteins; Reporting; Structure; Testing; Toxic effect; age related; alpha synuclein; genome-wide; protein aggregation; synuclein; synucleinopathy

Aggregation of a-synuclein is a characteristic event in Parkinsons disease and other synucleinopathies that show age-dependent progression. The aggregated forms of the protein are associated with the presence of Lewy bodies and other pathological events. It is not certain if Lewy bodies, or a-synuclein aggregation per se, are required for the disease process. What is clear is that a-synuclein can be a toxic protein in several cellular and animal models, although the molecular details of these events are not well understood. The aim of this project is to more clearly define what modifies a-synuclein aggregation and toxicity, and to try and understand why this is an age-related phenomenon. In the past reporting period, we have been actively involved in two projects related to the toxicity of a-synuclein using cultured cells as model systems. We have shown that native a-synuclein, prepared in a manner that does not generate oligomeric species that are competent for assembly, are not toxic to cells in culture. This supports previous data suggesting that aggregation of synuclein drives toxicity, although it refines our previous view in that it shows that not all aggregation is the same. Secondly, we have made progress towards a genomewide screen for modifiers of a-synuclein toxicity. We have developed inducible cell lines where a-synuclein expression can be switched off or on; these lines are currently undergoing testing to see if they can be used to then find additional genes that can limit these toxic effects.

α-突触核蛋白的聚集是帕金森病和显示年龄依赖性进展的其他突触核蛋白病中的特征性事件。蛋白质的聚集形式与路易体和其他病理事件的存在相关。尚不确定路易体或α-突触核蛋白聚集本身是否是疾病过程所需的。清楚的是，α-突触核蛋白在几种细胞和动物模型中可能是一种毒性蛋白，尽管这些事件的分子细节还不清楚。该项目的目的是更清楚地定义是什么改变了α-突触核蛋白的聚集和毒性，并试图理解为什么这是一个与年龄相关的现象。 在过去的报告期内，我们积极参与了两个使用培养细胞作为模型系统的与α-突触核蛋白毒性相关的项目。我们已经表明，以不产生能够组装的寡聚物种类的方式制备的天然α-突触核蛋白对培养物中的细胞没有毒性。这支持了先前的数据，表明突触核蛋白的聚集驱动毒性，尽管它改进了我们先前的观点，因为它表明并非所有的聚集都是相同的。 第二，我们已经在全基因组筛选α-突触核蛋白毒性修饰剂方面取得了进展。我们已经开发出了可诱导的细胞系，其中α-突触核蛋白的表达可以关闭或打开;这些细胞系目前正在进行测试，看看它们是否可以用来寻找可以限制这些毒性作用的其他基因。