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Proteostasis regulators as potential rescuers of PMM2 activity.
- Source :
-
Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2020 Jul 01; Vol. 1866 (7), pp. 165777. Date of Electronic Publication: 2020 Mar 25. - Publication Year :
- 2020
-
Abstract
- 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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2020. Published by Elsevier B.V.)
- Subjects :
- 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
Mutation genetics
Pentacyclic Triterpenes
Phosphotransferases (Phosphomutases) antagonists & inhibitors
Phosphotransferases (Phosphomutases) genetics
Phosphotransferases (Phosphomutases) metabolism
Phosphotransferases (Phosphomutases) ultrastructure
Protein Folding
Proteostasis drug effects
Congenital Disorders of Glycosylation drug therapy
Phosphotransferases (Phosphomutases) deficiency
Proteostasis genetics
Triterpenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1879-260X
- Volume :
- 1866
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. Molecular basis of disease
- Publication Type :
- Academic Journal
- Accession number :
- 32222543
- Full Text :
- https://doi.org/10.1016/j.bbadis.2020.165777