Presentation description

Congenital Disorders of Glycosylation (CDGs), a group of rare genetic diseases, are caused by partial loss-of-function mutations in glycosylation pathways. Mutations in DPAGT1, a protein that spans the endoplasmic reticulum (ER) membrane and catalyzes the first step of N-linked glycosylation, can lead to cellular stress due to the misfolding of proteins. Pathogenic mutations in DPAGT1 result in DPAGT1-CDG, and this causes cognitive disability, movement disorders, and seizures. To address the lack of effective therapeutics, we conducted a drug screen using the Prestwick Chemical Library in a Drosophila model of DPAGT1-CDG using an eye-specific knockdown of DPAGT1. The DPAGT1-CDG model has small, rough eyes, and drugs that suppressed and enhanced the diseased phenotype were identified by measuring respective eye size. From this drug repurposing approach, we identified four enriched drug categories (dopaminergic antagonists, cyclooxygenase inhibitors, histamine antagonists, and thyroid antagonists) and validated these hits with dose-response curves. Additionally, we genetically validated these hits via gene knockdown to phenocopy the candidate drugs. Most strikingly, dopamine receptor 2 (D2) antagonists could be genetically phenocopied to strongly rescue the DPAGT1-CDG model. In addition, a drug that inhibits the ion transporter NKCC1 (Ncc69 ortholog in Drosophila), could rescue the DPAGT1-CDG phenotype pharmacologically and genetically. Further validation on neurologically impaired DPAGT1-CDG Drosophila and human cell line models has the potential to lead to new DPAGT1-CDG therapeutics. These findings offer new potential therapeutic targets for DPAGT1-CDG and help reveal a novel relationship between biological pathways that modulate the DPAGT1-CDG phenotype.