Loading...
Mapping ERAD Substrate Selection Under Glycosylation Stress in Rare Disease Models of DPAGT1-CDG
Citations
Altmetric:
Abstract
Glycosylation is an essential biological pathway that involves the co- and post-translational modification of proteins, determining their structure, functionality, and folding. Mutations in glycosylation-related genes lead to improper protein folding, resulting in rare conditions known as Congenital Disorders of Glycosylation (CDGs). DPAGT1-CDG is an autosomal recessive disorder caused by mutations in the DPAGT1 gene, which encodes the initial enzyme in N-glycosylation. This induces protein misfolding and accumulation within the ER, thereby eliciting cellular stress responses. Patients with DPAGT1-CDG experience severe symptoms, including neurodevelopmental delays, gastrointestinal complications, seizures, among others. Given the high mortality rate and the absence of curative treatments, there is a pressing medical need to identify effective therapeutic options promptly. Our laboratory utilizes Drosophila melanogaster and RPE-1 cell culture to develop disease models of DPAGT1-CDG. Previously, we identified key pathways that enhance the survival of D. melanogaster following DPAGT1 inhibition, notably two quality control systems: endoplasmic reticulum-associated degradation (ERAD) and the unfolded protein response (UPR). Our objective is to elucidate how ERAD modulates substrate recognition under glycosylation stress and to identify a therapeutic target for an FDA-approved drug. The UPR is activated by ER sensor proteins—IRE1, PERK, and ATF6—to initiate downstream signaling pathways and promote transcription of ERAD, autophagy, and apoptosis. We find that RNAi knockdown of ERAD components (HRD1, SEL1L, EDEM1/2, VCP) rescues the disease phenotype in vivo. We hypothesize that under glycosylation stress, ERAD is overburdened and unable to process proteins as quickly as they are synthesized. Notably, VCP, a component of ERAD, demonstrated improvement when knocked down and when overexpressed in the disease model. VCP participates in two distinct ERAD complexes: ERAD-lumen, involved in degrading proteins, and ERAD-cytosol, which regulates autophagy. Furthermore, knockdown of the autophagy regulator BECLIN-1, along with ubiquitin-proteasome cofactors NPLOC4, YOD1, and PLAA, rescued the disease phenotype. This research will provide insights into the interplay between glycosylation, ERAD, and autophagy, thereby enhancing our understanding of the underlying mechanisms and guiding the development of novel therapeutic strategies.
Description
These are the slides from a presentation given at the Annual Drosophila Research Conference held in Chicago, Illinois on 03/06/2026.
Date
2026-03-06
Journal Title
Journal ISSN
Volume Title
Publisher
University of Kansas
Files
Loading...
WildM_2026.pdf
Adobe PDF, 1.66 MB
Research Projects
Organizational Units
Journal Issue
Keywords
Cell Stress, Rare Disease, Drosophila, ERAD, Glycosylation