Authors:
Sarah Iqbal, Shannon Howard, and Philip V. LoGrasso
Summary:
Serum glucocorticoid kinase 1 (SGK1) has been shown to be protective in models of Parkinson's disease, but the details by which it confers benefit is unknown. The current study was designed to investigate the details by which SGK1 confers neuroprotection. To do this we employed a cellular neurodegeneration model to investigate JNK signaling and endoplasmic reticulum (ER) stress induced by 6-hydroxydopamine. SGK1 adenovirus was created and used to over-express SGK1 in SHSY5Y cells and dexamethasone was used to increase endogenous expression of SGK1. Oxidative stress, mitochondrial dysfunction, and cell death were monitored to test the protective effect of SGK1. To investigate the effect of SGK1 over-expression in vivo, SGK1 adenovirus was injected into the striatum of mice treated with1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and protection of dopaminergic neurons was quantitatively assessed by tyrosine hydroxylase immunohistochemistry. SGK1 over-expression was found to decrease reactive oxygen species generation, alleviate mitochondrial dysfunction, and rescue cell death in vitro and in vivo by inactivating MKK4, JNK, and GSK3β and thereby decreasing ER and oxidative stress. These results suggest therapeutic strategies for activation of SGK1 may have the potential to be neuroprotective by deactivating the JNK and GSK3β pathways.
Source:
Molecular & Cellular Biology; on-line March 30, 2015