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A genome-wide imaging-based screening to identify genes involved in synphilin-1 inclusion formation in Saccharomyces cerevisiae

Journal article
Authors Lin-Ling Zhao
Q. Yang
J. Zheng
Xuefeng Zhu
X. X. Hao
J. Song
T. Lebacq
V. Franssens
J. Winderickx
Thomas Nyström
B. D. Liu
Published in Scientific Reports
Volume 6
ISSN 2045-2322
Publication year 2016
Published at Department of Chemistry and Molecular Biology
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Language en
Links dx.doi.org/10.1038/srep30134
Keywords sister-chromatid cohesion, alpha-synuclein, parkinsons-disease, lewy, bodies, cytosolic chaperonin, aggresome formation, actin cytoskeleton, yeast, protein, aggregation
Subject categories Clinical Medicine

Abstract

Synphilin-1 is a major component of Parkinson's disease (PD) inclusion bodies implicated in PD pathogenesis. However, the machinery controlling synphilin-1 inclusion formation remains unclear. Here, we investigated synphilin-1 inclusion formation using a systematic genome-wide, high-content imaging based screening approach (HCI) in the yeast Saccharomyces cerevisiae. By combining with a secondary screening for mutants showing significant changes on fluorescence signal intensity, we filtered out hits that significantly decreased the expression level of synphilin-1. We found 133 yeast genes that didn't affect synphilin-1 expression but that were required for the formation of synphilin-1 inclusions. Functional enrichment and physical interaction network analysis revealed these genes to encode for functions involved in cytoskeleton organization, histone modification, sister chromatid segregation, glycolipid biosynthetic process, DNA repair and replication. All hits were confirmed by conventional microscopy. Complementation assays were performed with a selected group of mutants, results indicated that the observed phenotypic changes in synphilin-1 inclusion formation were directly caused by the loss of corresponding genes of the deletion mutants. Further growth assays of these mutants showed a significant synthetic sick effect upon synphilin-1 expression, which supports the hypothesis that matured inclusions represent an end stage of several events meant to protect cells against the synphilin-1 cytotoxicity.

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