PXD050018-1

PXD050018 is an original dataset announced via ProteomeXchange.

Title	Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different congenital disorders of glycosylation
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.
HostingRepository	PRIDE
AnnounceDate	2024-11-13
AnnouncementXML	Submission_2024-11-13_11:16:05.279.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Akhilesh Pandey
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-02-21 19:04:22	ID requested
⏵ 1	2024-11-13 11:16:06	announced

Budhraja R, Radenkovic S, Jain A, Muffels IJJ, Ismaili MHA, Kozicz T, Pandey A, Morava E, Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different congenital disorders of glycosylation. Mol Genet Metab, 142(2):108487(2024) [pubmed]

10.1016/j.ymgme.2024.108487;

submitter keyword: glycosylation, glycoproteomics, GLM101,Congenital disorders of glycosylation, therapy, PMM2-CDG

Akhilesh Pandey
contact affiliation	Department of Laboratory Medicine and Pathology Mayo Clinic, Rochester, Minnesota 55905 United States
contact email	pandey.akhilesh@mayo.edu
lab head
Akhilesh Pandey
contact affiliation	Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905
contact email	pandey.akhilesh@mayo.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD050018
     1. Label: PRIDE project
     2. Name: Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different congenital disorders of glycosylation