PT  - JOURNAL ARTICLE
AU  - Tamy Portillo Rodriguez
AU  - Joshua D. Mast
AU  - Tom Hartl
AU  - Ethan O. Perlstein
TI  - Defects in the neuroendocrine axis cause global development delay in a <em>Drosophila</em> model of NGLY1 Deficiency
AID  - 10.1101/241653
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 241653
4099  - http://biorxiv.org/content/early/2018/01/01/241653.short
4100  - http://biorxiv.org/content/early/2018/01/01/241653.full
AB  - 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.