Reference : Phenotypic assays in yeast and zebrafish reveal drugs that rescue ATP13A2 deficiency
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Systems Biomedicine
http://hdl.handle.net/10993/43792
Phenotypic assays in yeast and zebrafish reveal drugs that rescue ATP13A2 deficiency
English
Heins Marroquin, Ursula mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Jung, Paul mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Cordero Maldonado, Maria Lorena mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Crawford, Alexander mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > > ; Norwegian University of Life Sciences > Faculty of Veterinary Medicine > > ; Institute for Orphan Drug Discovery, > Bremer Innovations- und Technologiezentrum,]
Linster, Carole mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
27-Sep-2019
Brain Communications
Oxford University Press
1
1
2-17
Yes
International
2632-1297
2632-1297
Oxford
UK
[en] ATP13A2 ; budding yeast ; drug screening ; heavy metals ; zebrafish
[en] Mutations in ATP13A2 (PARK9) are causally linked to the rare neurodegenerative disorders Kufor-Rakeb syndrome, hereditary spastic paraplegia and neuronal ceroid lipofuscinosis. This suggests that ATP13A2, a lysosomal cation-transporting ATPase, plays a crucial role in neuronal cells. The heterogeneity of the clinical spectrum of ATP13A2-associated disorders is not yet well understood and currently these diseases remain without effective treatment. Interestingly, ATP13A2 is widely conserved among eukaryotes, and the yeast model for ATP13A2 deficiency was the first to indicate a role in heavy metal homeostasis, which was later confirmed in human cells. Here we show that deletion of YPK9 (the yeast ortholog of ATP13A2) in Saccharomyces cerevisiae leads to growth impairment in the presence of Zn2+, Mn2+, Co2+ and Ni2+, with the strongest phenotype being observed in the presence of zinc. Using the ypk9 mutant, we developed a high-throughput growth rescue screen based on the Zn2+ sensitivity phenotype. Screening of two drug libraries identified 11 compounds that rescued growth. Subsequently, we generated a zebrafish model for ATP13A2 deficiency and found that both partial and complete loss of atp13a2 function led to increased sensitivity to Mn2+. Based on this phenotype, we validated two of the FDA-approved drugs found in the yeast screen to also exert a rescue effect in zebrafish – N-acetylcysteine, a potent antioxidant, and furaltadone, a nitrofuran antibiotic. This study further supports that combining the high-throughput screening capacity of yeast with rapid in vivo drug testing in zebrafish can represent an efficient drug repurposing strategy in the context of rare inherited disorders involving conserved genes. This work also deepens the understanding of the role of ATP13A2 in heavy metal detoxification and provides a new in vivo model for investigating ATP13A2 deficiency.
Luxembourg Centre for Systems Biomedicine (LCSB): Enzymology & Metabolism (Linster Group)
Researchers ; Professionals ; Students ; General public
http://hdl.handle.net/10993/43792
10.1093/braincomms/fcz019
https://doi.org/10.1093/braincomms/fcz019
The original publication is available at https://academic.oup.com/braincomms

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