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Defects in the neuroendocrine axis cause global development delay in a Drosophila model of NGLY1 Deficiency

Tamy Portillo Rodriguez, View ORCID ProfileJoshua D. Mast, Tom Hartl, View ORCID ProfileEthan O. Perlstein
doi: https://doi.org/10.1101/241653
Tamy Portillo Rodriguez
Perlara PBC, 6000 Shoreline Court, Suite 204, South San Francisco, California 94080, United States
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Joshua D. Mast
Perlara PBC, 6000 Shoreline Court, Suite 204, South San Francisco, California 94080, United States
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  • ORCID record for Joshua D. Mast
Tom Hartl
Perlara PBC, 6000 Shoreline Court, Suite 204, South San Francisco, California 94080, United States
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Ethan O. Perlstein
Perlara PBC, 6000 Shoreline Court, Suite 204, South San Francisco, California 94080, United States
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  • ORCID record for Ethan O. Perlstein
  • For correspondence: ethan@perlara.com
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ABSTRACT

N-glycanase 1 (NGLY1) Deficiency is a rare monogenic multi-system disorder first described in 2014. NGLY1 is evolutionarily conserved in model organisms, including the Drosophila melanogaster NGLY1 homolog, Pngl. Here we conducted a natural history study and chemical-modifier screen on a new fly model of NGLY1 Deficiency engineered with a nonsense mutation in Pngl at codon 420, resulting in truncation of the C-terminal carbohydrate-binding PAW domain. Homozygous mutant animals exhibit global development delay, pupal lethality and small body size as adults. We developed a 96-well-plate, image-based, quantitative assay of Drosophila larval size for use in a screen of the 2,650-member Microsource Spectrum compound library of FDA approved drugs, bioactive tool compounds, and natural products. We found that the cholesterol-derived ecdysteroid molting hormone 20-hydroxyecdysone (20E) rescued the global developmental delay in mutant homozygotes. Targeted expression of a human NGLY1 transgene to tissues involved in ecdysteroidogenesis, e.g., prothoracic gland, also rescues global developmental delay in mutant homozygotes. Finally, the proteasome inhibitor bortezomib is a potent enhancer of global developmental delay in our fly model, evidence of a defective proteasome “bounce-back” response that is also observed in nematode and cellular models of NGLY1 Deficiency. Together, these results demonstrate the therapeutic relevance of a new fly model of NGLY1 Deficiency for drug discovery, biomarker discovery, pharmacodynamics studies, and gene modifier screens.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 01, 2018.
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Defects in the neuroendocrine axis cause global development delay in a Drosophila model of NGLY1 Deficiency
Tamy Portillo Rodriguez, Joshua D. Mast, Tom Hartl, Ethan O. Perlstein
bioRxiv 241653; doi: https://doi.org/10.1101/241653
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Defects in the neuroendocrine axis cause global development delay in a Drosophila model of NGLY1 Deficiency
Tamy Portillo Rodriguez, Joshua D. Mast, Tom Hartl, Ethan O. Perlstein
bioRxiv 241653; doi: https://doi.org/10.1101/241653

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