The research group U746 CIBERER from Madrid led by Dr. Belén Pérez just published very promising results of aa possible therapeutics strategy for PMM2-CDG. Even though this is the most frequent Congenital Disorders of Glycosylation (CDG) type affecting about 1000 people worldwide, there is still no treatment for this condition.
PMM2-CDG is caused by a genetic defect in the phosphomannomutase 2 (PMM2) protein that causes loss of function of this protein, responsible for several and diverse clinical presentations. The main reason for this lack of function is the incorrect folding when the protein is produced.
Dr. Bélen's team evaluated the effect of proteostasis regulators in the stability and activity of several variants of PMM2 and showed their potential to rescue the PMM2 defect. This study, published in Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, showed that treatment of cellular models with celastrol, one of the molecules under study, increased both the quantity of protein and its activity. This was accompanied by an increase in the levels of protein and gene expression of Heat Shock Proteins (Hsps). In fact, the Hsp90 seems to be the main responsible behind PMM2 stabilization.
This proof of concept is a very exciting development for the CDG community as it demonstrate the potential of proteostasis regulators to treat PMM2-CDG by stabilizing the PMM2 protein.
Proteostasis regulators as potential rescuers of PMM2 activity. A.Vilas, P.Yuste-Checa, D.Gallego, L.R.Desviat, M.Ugarte, C.Pérez-Cerda, A.Gámez, B.Pérez. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. doi: 10.1016/j.bbadis.2020.165777