Tuesday, May 8, 2018

Characterization of a Drosophila model of NGLY1 deficiency

Defects in the Neuroendocrine Axis Contribute to Global Development Delay in a Drosophila Model of NGLY1 Deficiency

Tamy Portillo Rodriguez, Joshua D. Mast, Tom Hartl, Tom Lee, Peter Sand and Ethan O. Perlstein
G3: GENES, GENOMES, GENETICS Early online May 7, 2018; https://doi.org/10.1534/g3.118.300578

From the abstract: "N-glycanase 1 (NGLY1) Deficiency is a rare monogenic multi-system disorder ... Here we conducted a natural history study and chemical-modifier screen on the Drosophila melanogaster NGLY1 homolog, Pngl. We generated a new fly model of NGLY1 Deficiency, engineered with a nonsense mutation in Pngl at codon 420 that results in a 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 found that the cholesterol-derived ecdysteroid molting hormone 20-hydroxyecdysone (20E) partially 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 partially rescues global developmental delay in mutant homozygotes. Finally, the proteasome inhibitor bortezomib is a potent enhancer of global developmental delay in our fly model ... Together, these results demonstrate the therapeutic relevance of a new fly model of NGLY1 Deficiency for drug discovery and gene modifier screens."

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