期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1863, 期 12, 页码 3286-3293出版社
ELSEVIER
DOI: 10.1016/j.bbadis.2017.08.023
关键词
Classic Galactosemia; PI3K/Akt signaling; Endoplasmic reticulum (ER) stress; Salubrinal; Primary ovarian insufficiency (POI); Cerebellar ataxia
资金
- University of Colorado Denver Department of OB/GYN Division of Reproductive Endocrinology and Infertility
- Division of Reproductive Sciences Research Funds
- NIH [1 R01 HD074844]
- Primary Children's Hospital Foundation (Intermountain Healthcare) [K2R2R]
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 GaIT-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 GaIT-deficient mouse tissues. In mutant mouse ovaries, phospho-Akt [pAkt (Ser473)] and pGsk3 beta were reduced by 62.5% and 93.5%, respectively (p < 0.05 versus normal controls). In mutant cerebella, pAkt (Ser473) and pGsk3 beta 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.
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