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New therapeutic strategy for the most common congenital defect of glycosylation (CDG) evidenced in cell models

Investigación en laboratorio
Wednesday, June 10, 2020

A team led by CIBERER researcher Belén Pérez has confirmed that proteostasis regulators may be key to develop a therapeutic approach for the most common congenital defect of glycosylation (CDG), phosphomanomutase-2 deficiency (PMM2-CDG). The experiments have been conducted in cellular models of the disease. This rare metabolic pathology affects around 1,000 people worldwide and causes cerebellum dysfunction, abnormal fat distribution, inverted nipples, squint and hypotonia.

In patients with the mutated PMM2 gene, the loss of enzymatic function is mainly attributed to the incorrect folding of the protein. Therefore, using compounds that may help correct these folding errors, such as proteostasis regulators and/or chaperones, could lead to a recovered function in PMM2-CDG. This is precisely what Dr. Belén Pérez’s team has studied. Researchers have tested two different compounds (celastrol and MG132) in several cell lines that had different mutations of the PMM2 protein.

According to the study, cerastrol had a positive effect in terms of protein content and enzymatic activity of PMM2-CDG, while MG123 did not have a significant effect in any of the cell lines.

These results suggest that the use of proteostasis regulators may be a promising therapeutic approach to treat this type of CDG, which affects 80% of the patients with a congenital defect of glycosilation.

Acces to the original article: Proteostasis regulators as potential rescuers of PMM2 activity. Biochimica et Biophysica Acta - Molecular Basis of Disease.

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