Dataset Information

Mitochondrial dysfunction is a driver of cardiac complications in PGM1-CDG with implications for therapy

ABSTRACT: Phosphoglucomutase 1 (PGM1) enzyme plays a central role in metabolism, by bridging glycolysis, glycogen metabolism and glycosylation. PGM1 deficiency is a rare congenital disorder of glycosylation (CDG) known for its unusually high incidence of lethal cardiac complications. While the role of PGM1 in glycosylation has been partially elucidated, little is known about the role of PGM1 in the heart. Similarly, while the current therapy such as D-galactose supplementation is able to treat the glycosylation aspect of PGM1-deficiency, there is no treatment for the cardiac complications in this disorder. Therefore, there is a critical need to understand the role of PGM1 in the heart and propose new cardiac-specific therapies. Here, by leveraging multiomics approach on human induced pluripotent stem cell-derived cardiomyocytes (iCMs) from individuals with PGM1 deficiency, we show that PGM1 deficiency results in profound changes in energy metabolism and extracellular matrix (ECM). Moreover, by in silico drug repurposing, we identify several drug candidates that might treat cardiac failure possibly by upregulating energy metabolism and downregulating ECM and improve the clinical outcome in affected individuals.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Akhilesh Pandey

LAB HEAD: Akhilesh Pandey

PROVIDER: PXD057756 | Pride | 2026-02-09

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	10123_RB_PGM1_CMs_NGP_10.raw	Raw
	10123_RB_PGM1_CMs_NGP_11.raw	Raw
	10123_RB_PGM1_CMs_NGP_12.raw	Raw
	10123_RB_PGM1_CMs_NGP_1_20231018210016.raw	Raw
	10123_RB_PGM1_CMs_NGP_2.raw	Raw

Items per page:

1 - 5 of 27

Publications

Are viral vector-mediated therapies compatible with aberrant glycosylation?

Muffels I J J IJJ Budhraja R R Radenkovic S S Shah R R Pandey A A Morava E E Kozicz T T

Molecular therapy. Methods & clinical development 20250722 3

The ability of adeno-associated viruses (AAVs) to transduce host cells relies on interactions with glycan moieties on the cellular surface. Consequently, disrupted protein glycosylation, which is seen in a range of neurodevelopmental and neurodegenerative diseases, could impair transduction efficiency. Understanding how altered glycosylation impacts AAV binding is essential to optimize AAV-mediated therapeutic strategies. We used glycoproteomics data from cortical brain organoids and iCardiomyoc ...[more]

PMID: 40809676

Similar Datasets

Project description:Phosphomannomutase 2 (PMM2) converts mannose-6-phospahate to mannose-1-phosphate; the substrate for GDP-mannose, a building block of the glycosylation biosynthetic pathway. Pathogenic variants in the PMM2 gene have been shown to be associated with protein hypoglycosylation causing PMM2-congenital disorder of glycosylation (PMM2-CDG). While mannose supplementation improves glycosylation in vitro, but not in vivo, we hypothesized that liposomal delivery of mannose-1-phosphate could increase the stability and delivery of the activated sugar to enter the targeted compartments of cells. Thus, we studied the effect of liposome-encapsulated mannose-1-P (GLM101) on global protein glycosylation and on the cellular proteome in skin fibroblasts from individuals with PMM2-CDG, as well as in individuals with two N-glycosylation defects early in the pathway, namely ALG2-CDG and ALG11-CDG. We leveraged multiplexed proteomics and N-glycoproteomics in fibroblasts derived from different individuals with various pathogenic variants in PMM2, ALG2 and ALG11 genes. Proteomics data revealed a moderate but significant change in the abundance of some of the proteins in all CDG fibroblasts upon GLM101 treatment. On the other hand, N-glycoproteomics revealed the GLM101 treatment enhanced the expression levels of several high-mannose and complex/hybrid glycopeptides from numerous cellular proteins in individuals with defects in PMM2 and ALG2 genes. Both PMM2-CDG and ALG2-CDG exhibited several-fold increase in glycopeptides bearing Man6 and higher glycans and a decrease in Man5 and smaller glycan moieties, suggesting that GLM101 helps in the formation of mature glycoforms. These changes in protein glycosylation were observed in all individuals irrespective of their genetic variants. ALG11-CDG fibroblasts also showed increase in high mannose glycopeptides upon treatment; however, the improvement was not as dramatic as the other two CDG. Overall, our findings suggest that treatment with GLM101 overcomes the genetic block in the glycosylation pathway and can be used as a potential therapy for CDG with enzymatic defects in early steps in protein N-glycosylation.