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See detailPhenotypic assays in yeast and zebrafish reveal drugs that rescue ATP13A2 deficiency
Heins Marroquin, Ursula UL; Jung, Paul UL; Cordero Maldonado, Maria Lorena UL et al

in Brain Communications (2019), 1(1), 2-17

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 ... [more ▼]

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. [less ▲]

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See detailDeep learning image recognition enables efficient genome editing in zebrafish by automated injections
Cordero Maldonado, Maria Lorena UL; Perathoner, Simon; van der Kolk, Kees-Jan et al

in PLoS ONE (2019)

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See detailGender-specific expression of ubiquitin-specific peptidase 9 modulates tau expression and phosphorylation: possible implications for tauopathies
Köglsberger, Sandra UL; Cordero Maldonado, Maria Lorena UL; Antony, Paul UL et al

in Molecular Neurobiology (2017), 54(10), 79797993

Public transcriptomics studies have shown that several genes display pronounced gender differences in their expression in the human brain, which may influence the manifestations and risk for neuronal ... [more ▼]

Public transcriptomics studies have shown that several genes display pronounced gender differences in their expression in the human brain, which may influence the manifestations and risk for neuronal disorders. Here we apply a transcriptome-wide analysis to discover genes with gender-specific expression and significant alterations in public post mortem brain tissue from Alzheimer’s disease (AD) patients compared to controls. We identify the sex-linked ubiquitin specific peptidase 9 (USP9) as an outstanding candidate gene with highly significant expression differences between the genders and male-specific under-expression in AD. Since previous studies have shown that USP9 can modulate the phosphorylation of the AD-associated protein MAPT, we investigate functional associations between USP9 and MAPT in further detail. After observing a high positive correlation between the expression of USP9 and MAPT in the public transcriptomics data, we show that USP9 knockdown results in significantly decreased MAPT expression in a DU145 cell culture model and a concentration-dependent decrease for the MAPT orthologs mapta and maptb in a zebrafish model. From the analysis of microarray and qRT-PCR experiments for the knockdown in DU145 cells and prior knowledge from the literature, we derive a data-congruent model for a USP9-dependent regulatory mechanism modulating MAPT expression via BACH1 and SMAD4. Overall, the analyses suggest USP9 may contribute to molecular gender differences observed in tauopathies and provide a new target for intervention strategies to modulate MAPT expression. [less ▲]

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