Proteostasis regulators as potential rescuers of PMM2 activity

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2020-07, Vol.1866 (7), p.165777-165777, Article 165777
• Main Authors: Vilas, A., Yuste-Checa, P., Gallego, D., Desviat, L.R., Ugarte, M., Pérez-Cerda, C., Gámez, A., Pérez, B.
• Format: Article
• Language: English
• Subjects: Congenital disorders of glycosylation; Congenital Disorders of Glycosylation - drug therapy; Congenital Disorders of Glycosylation - genetics; Congenital Disorders of Glycosylation - metabolism; Congenital Disorders of Glycosylation - pathology; Fibroblasts - drug effects; Glycosylation - drug effects; HSP70 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - genetics; Humans; Leupeptins - pharmacology; Molecular chaperones; Mutation - genetics; Pharmacological chaperones; Phosphotransferases (Phosphomutases) - antagonists & inhibitors; Phosphotransferases (Phosphomutases) - deficiency; Phosphotransferases (Phosphomutases) - genetics; Phosphotransferases (Phosphomutases) - metabolism; Phosphotransferases (Phosphomutases) - ultrastructure; PMM2-CDG; Protein Folding; Proteostasis - drug effects; Proteostasis - genetics; Proteostasis regulators; Triterpenes - pharmacology
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2020.165777

Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common N-glycosylation disorder. To date there is no treatment. Following the identification of a number of destabilizing pathogenic variants, our group suggested PMM2-CDG to be a conformational disease. The aim of the present study was to evaluate the possible use of proteostasis network regulators to increase the stability, and subsequently the enzymatic activity, of misfolded PMM2 mutant proteins. Patient-derived fibroblasts transduced with their own PMM2 folding or oligomerization variants were treated with different concentrations of the proteostasis regulators celastrol or MG132. Celastrol treatment led to a significant increase in mutant PMM2 protein concentration and activity, while MG132 had a small effect on protein concentration only. The increase in enzymatic activity with celastrol correlated with an increase in the transcriptional and proteome levels of the heat shock proteins Hsp90 and Hsp70. The use of specific Hsp70 or Hsp90 inhibitors showed the positive effect of celastrol on PMM2 stability and activity to occur through Hsp90-driven modulation of the proteostasis network. The synergistic effect of celastrol and a previously described pharmacological chaperone was also examined, and a mutation-dependent synergistic effect on PMM2 activity was noted. These results provide proof-of-concept regarding the potential treatment of PMM2-CDG by proteostasis regulators, either alone or in combination with pharmacological chaperones. •PMM2-CDG is a conformational disease.•Rescue of protein concentration and enzymatic activity with proteostasis regulators•Role of Hsp70 and Hsp90 in PMM2 folding•Potential treatment of PMM2-CDG with proteostasis regulators