Scientists from the Florida campus of The Scripps Research Institute (TSRI) have found how a widely known but little-studied enzyme protects brain cells in models of Parkinson’s disease.
These findings could provide valuable insight into the development of drug candidates that could protect brain cells in Parkinson’s and other neurodegenerative diseases.
The study, published recently online ahead of print by the journal Molecular and Cellular Biology, focuses on the enzyme known as serum glucocorticoid kinase 1 (SGK1).
“The overexpression of SGK1 provides neuron protection in both cell culture and in animal models,” said Philip LoGrasso, a TSRI professor who led the study. “It decreases reactive oxygen species generation and alleviates mitochondrial dysfunction.”
Using a neurotoxin animal model of neurodegeneration, the study showed that SGK1 protects brain cells by blocking several pathways involved in neurodegeneration, deactivating other molecules known as JNK, GSK3β and MKK4.
Increasing SGK1 offers a potential therapeutic strategy because, as the study makes clear, there isn’t enough naturally occurring SGK1 to do the job.
“Even though the levels of naturally occurring SGK1 increases in the cell under stress, it was not enough to promote cell survival in our neurodegeneration model,” said Sarah Iqbal, the first author of the study and a member of the LoGrasso lab. “On the other hand, cell survival mechanisms tend to dominate when more SGK1 is added to the neurons.”
The LoGrasso lab plans to continue to explore SGK1 as a therapeutic possibility for Parkinson’s disease.
About this Parkinson’s disease research
Funding: The work was supported by the Department of Defense (grant W81XWH-12-1-0431), the National Institutes of Health (grants U01-NS057153 and GM103825), the Michael J Fox Foundation/23&Me, the Saul and Theresa Esman Foundation and a gift from the McCubbin Family.
Source: David March – Scripps Research Institute
Original Research: Abstract for “Serum- glucocorticoid-inducible kinase 1 confers protection in cell-based and in in vivo neurotoxin models via the c-Jun N-terminal kinase signaling pathway” by Sarah Iqbal, Shannon Howard and Philip V. LoGrasso in Molecular and Cellular Biology. Published online April 15 2015 doi:10.1128/MCB.01510-14
Abstract
Serum- glucocorticoid-inducible kinase 1 confers protection in cell-based and in in vivo neurotoxin models via the c-Jun N-terminal kinase signaling pathway
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.
“Serum- glucocorticoid-inducible kinase 1 confers protection in cell-based and in in vivo neurotoxin models via the c-Jun N-terminal kinase signaling pathway” by Sarah Iqbal, Shannon Howard and Philip V. LoGrasso in Molecular and Cellular Biology. Published online April 15 2015 doi:10.1128/MCB.01510-14
