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

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.

Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - August 27, 2017 Category: Molecular Biology Source Type: research