Unbiased Screens for Modifiers of Alpha-Synuclein Toxicity

Purpose of ReviewWe provide an overview about unbiased screens to identify modifiers of alpha-synuclein (Syn)-induced toxicity, present the models and the libraries that have been used for screening, and describe how hits from primary screens were selected and validated.Recent FindingsScreens can be classified as either genetic or chemical compound modifier screens, but a few screens do not fit this classification. Most screens addressing Syn-induced toxicity, including genome-wide overexpressing and deletion, were performed in yeast. More recently, newer methods such as CRISPR-Cas9 became available and were used for screening purposes. Paradoxically, given that Syn-induced toxicity plays a role in neurological diseases, there is a shortage of human cell-based models for screening. Moreover, most screens used mutant or fluorescently tagged forms of Syn and only very few screens investigated wild-type Syn. Particularly, no genome-wide Syn toxicity screen in human dopaminergic neurons has been published so far.SummaryMost unbiased screens for modifiers of Syn toxicity were performed in yeast, and there is a lack of screens performed in human and particularly dopaminergic cells.