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ZFIN ID: ZDB-PUB-170610-12
Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of MAP2K5 kinase as a potential drug target
Jo, M., Chung, A.Y., Yachie, N., Seo, M., Jeon, H., Nam, Y., Seo, Y., Kim, E., Zhong, Q., Vidal, M., Park, H.C., Roth, F., Suk, K.
Date: 2017
Source: Genome research   27(9): 1487-1500 (Journal)
Registered Authors: Chung, Ah-Young, Kim, Eunmi, Park, Hae-Chul
Keywords: none
MeSH Terms:
  • Amyotrophic Lateral Sclerosis/genetics*
  • Amyotrophic Lateral Sclerosis/pathology
  • Amyotrophic Lateral Sclerosis/therapy
  • Animals
  • Humans
  • MAP Kinase Kinase 5/genetics*
  • Molecular Targeted Therapy
  • Mutant Proteins/genetics
  • Mutation/genetics
  • Protein Interaction Maps/genetics
  • Ribonuclease, Pancreatic/genetics*
  • Saccharomyces cerevisiae/genetics
  • Sequence Deletion/genetics
  • Transcription Factor TFIIIA/genetics*
  • Zebrafish/genetics
PubMed: 28596290 Full text @ Genome Res.
To understand disease mechanisms, a large-scale analysis of human-yeast genetic interactions was performed. Of 1305 human disease genes assayed, 20 genes exhibited strong toxicity in yeast. Human-yeast genetic interactions were identified by en masse transformation of the human disease genes into a pool of 4653 homozygous diploid yeast deletion mutants with unique barcode sequences, followed by multiplexed barcode sequencing to identify yeast toxicity modifiers. Subsequent network analyses focusing on amyotrophic lateral sclerosis (ALS)-associated genes, such as optineurin (OPTN) and angiogenin (ANG), showed that the human orthologs of the yeast toxicity modifiers of these ALS genes are enriched for several biological processes, such as cell death, lipid metabolism, and molecular transport. When yeast genetic interaction partners held in common between human OPTN and ANG were validated in mammalian cells and zebrafish, MAP2K5 kinase emerged as a potential drug target for ALS therapy. The toxicity modifiers identified in this study may deepen our understanding of the pathogenic mechanisms of ALS and other devastating diseases.