Reversal of aberrant PI3K/Akt signaling by Salubrinal in a GalT-deficient mouse model.

Abstract

Classic Galactosemia is an autosomal recessive disorder caused by deleterious mutations in the GALT gene, which encodes galactose-1 phosphate uridylyltransferase enzyme (GALT: EC 2.7.7.12). Recent studies of primary skin fibroblasts isolated from the GalT-deficient mice demonstrated a slower growth rate, a higher level of endoplasmic reticulum (ER) stress, and down-regulation of the Phosphoinositide 3 kinase/Protein kinase B (PI3K/Akt) signaling pathway. In this study, we compared the expression levels of the PI3K/Akt signaling pathway in normal and GalT-deficient mouse tissues. In mutant mouse ovaries, phospho-Akt [pAkt (Ser473)] and pGsk3β were reduced by 62.5% and 93.5%, respectively (p<0.05 versus normal controls). In mutant cerebella, pAkt (Ser473) and pGsk3β were reduced by 62%, 50%, respectively (p<0.05). To assess the role of ER stress in the down-regulation of PI3K/Akt signaling, we examined if administration of Salubrinal, a chemical compound that alleviates ER stress, to GalT-deficient fibroblasts and animals could normalize the pathway. Our results demonstrated that Salubrinal effectively reversed the down-regulated PI3K/Akt signaling pathway in the mutant cells and animals to levels close to those of their normal counterparts. Moreover, we revealed that Salubrinal can significantly slow down the loss of Purkinje cells in the cerebella, as well as the premature loss of primordial ovarian follicles in young mutant mice. These results open the door for a new therapeutic approach for the patients with Classic Galactosemia.

• Authors: B Balakrishnan, C Nicholas, A Siddiqi, W Chen, E Bales, M Feng, J Johnson, K Lai
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1863 Issue 12 Pg. 3286-3293 (12 2017) ISSN: 0925-4439 [Print] Netherlands
• PMID: 28844959 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Cinnamates
• salubrinal
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• UTP-Hexose-1-Phosphate Uridylyltransferase
• Thiourea

Topics

• Animals
• Cinnamates (pharmacology)
• Disease Models, Animal
• Down-Regulation
• Endoplasmic Reticulum Stress
• Female
• Fibroblasts (metabolism)
• Galactosemias (genetics, metabolism)
• Mice
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Purkinje Cells (drug effects)
• Signal Transduction (drug effects)
• Thiourea (analogs & derivatives, pharmacology)
• UTP-Hexose-1-Phosphate Uridylyltransferase