Alpha Synuclein, cellular dysfunction and Parkinson disease

α-突触核蛋白的聚集是帕金森病和其他表现出年龄相关性进展的突触核病的特征事件。蛋白质的聚集形式与路易小体和其他病理事件的存在有关。目前还不确定路易小体或α-突触核蛋白聚集本身是否是疾病过程所必需的。很清楚的是，在几种细胞和动物模型中，α-突触核蛋白可能是一种有毒蛋白质，尽管这些事件的分子细节还没有被很好地理解。这个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。 在过去的报告期间，我们积极参与了两个与a-突触核蛋白毒性有关的项目，使用培养细胞作为模型系统。我们已经证明，天然的a-突触核蛋白，以不产生能够组装的寡聚物种的方式制备，对培养的细胞没有毒性。这支持了之前的数据，即突触核蛋白的聚集会驱动毒性，尽管它精炼了我们之前的观点，因为它表明并不是所有的聚集都是相同的。 其次，我们在全基因组范围内筛选α-突触核蛋白毒性的修饰物方面取得了进展。我们已经开发了可诱导的细胞系，其中α-突触核蛋白的表达可以被关闭或打开；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额外的基因来限制这些毒性效应。

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.