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Unbiased Screens for Modifiers of Alpha-Synuclein Toxicity

  • Genetics (V Bonifati, Section Editor)
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Abstract

Purpose of Review

We provide an overview about unbiased screens to identify modifiers of alpha-synuclein (αSyn)-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 Findings

Screens can be classified as either genetic or chemical compound modifier screens, but a few screens do not fit this classification. Most screens addressing αSyn-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 αSyn-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 αSyn and only very few screens investigated wild-type αSyn. Particularly, no genome-wide αSyn toxicity screen in human dopaminergic neurons has been published so far.

Summary

Most unbiased screens for modifiers of αSyn toxicity were performed in yeast, and there is a lack of screens performed in human and particularly dopaminergic cells.

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Funding

This work was supported by the BMBF-funded project “HitTau” (01EK1605A to G.U.H.), the Deutsche Forschungsgemeinschaft (DFG, HO2402/18-1, Munich Cluster for Systems Neurology SyNergy) (to G.U.H.), the NOMIS foundation (FTLD project to G.U.H.), and the Parkinson Fonds Deutschland (α-synuclein high-throughput screening to G.U.H. and M.H.).

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Authors and Affiliations

  1. Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), 81377, Munich, Germany

    Matthias Höllerhage & Günter U. Höglinger

  2. Department of Neurology, Technical University of Munich (TUM), 81675, Munich, Germany

    Matthias Höllerhage & Günter U. Höglinger

  3. HT-Technology Development Studio, Max Planck Institute of Molecular Cell Biology and Genetics, 01307, Dresden, Germany

    Marc Bickle

  4. Munich Cluster for Systems Neurology (SyNergy), Ludwig Maximilians University (LMU), 81377, Munich, Germany

    Günter U. Höglinger

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  1. Matthias Höllerhage
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Correspondence to Günter U. Höglinger.

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Günter Höglinger and Matthias Höllerhage each declare no potential conflict of interest.

Marc Bickle reports a fee for service from DZNE, during the conduct of the study.

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Höllerhage, M., Bickle, M. & Höglinger, G.U. Unbiased Screens for Modifiers of Alpha-Synuclein Toxicity. Curr Neurol Neurosci Rep 19, 8 (2019). https://doi.org/10.1007/s11910-019-0925-z

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