Researchers at the Florida campus of The Scripps Research Institute (TSRI) have identified how the enzyme serum glucocorticoid kinase 1 (SGK1) protects neurons in laboratory and animal models of Parkinson’s disease.
These findings improve our understanding of cellular mechanisms that can guard brain cells against neurodegeneration and could guide development of drug candidates aimed at protecting neurons in Parkinson’s disease and related disorders.
The study, published online in the journal Molecular and Cellular Biology, centers on SGK1, an enzyme previously noted in Parkinson’s models but not well characterized for its protective actions.
“Overexpressing SGK1 provides robust protection to neurons in both cultured cells and animal models,” said Philip LoGrasso, a TSRI professor who led the research. “SGK1 reduces the generation of reactive oxygen species and helps reverse mitochondrial dysfunction that contributes to neuronal death.”
Using a neurotoxin-based model of neurodegeneration, the researchers showed that higher SGK1 activity blocks multiple pathways implicated in neuronal injury. Specifically, SGK1 overexpression inactivated key signaling molecules including JNK, GSK3β and MKK4, signaling routes known to mediate stress responses, apoptosis and mitochondrial damage in neurons.
The study suggests that natural levels of SGK1 in neurons under stress are insufficient to prevent degeneration. While cells respond to stress by raising endogenous SGK1, that increase did not fully support cell survival in the neurodegeneration models used.
“Although stress elevates the cell’s own SGK1, that endogenous response was not enough to promote meaningful survival in our models,” said Sarah Iqbal, the study’s first author and a member of the LoGrasso laboratory. “When additional SGK1 was supplied experimentally, cellular survival mechanisms became dominant and neurons were better protected.”
These results point to therapeutic strategies that raise SGK1 activity or mimic its effects as potential avenues to limit neuronal loss. The LoGrasso lab intends to continue investigating SGK1’s therapeutic potential for Parkinson’s disease, focusing on how activation of this kinase might be harnessed safely and effectively in patients.
About this Parkinson’s disease research
Funding: This work received support from multiple sources, including the U.S. Department of Defense (grant W81XWH-12-1-0431), the National Institutes of Health (grants U01-NS057153 and GM103825), the Michael J. Fox Foundation/23andMe, the Saul and Theresa Esman Foundation, and a gift from the McCubbin Family.
Source: David March – Scripps Research Institute
Original Research: Iqbal S., Howard S., and LoGrasso P. V., “Serum-glucocorticoid-inducible kinase 1 confers protection in cell-based and in vivo neurotoxin models via the c-Jun N-terminal kinase signaling pathway,” 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 vivo neurotoxin models via the c-Jun N-terminal kinase signaling pathway
SGK1 has shown protective effects in Parkinson’s disease models, but the mechanisms responsible for this protection were not fully defined. This study examined how SGK1 mediates neuroprotection by using a cellular model of neurodegeneration triggered with 6-hydroxydopamine, focusing on c-Jun N-terminal kinase (JNK) signaling and endoplasmic reticulum (ER) stress. An adenoviral vector encoding SGK1 was used to overexpress the kinase in SH-SY5Y neuronal cells, and dexamethasone was used to induce endogenous SGK1 expression. Researchers then measured oxidative stress, mitochondrial function, and cell viability to evaluate protective effects. To assess in vivo relevance, SGK1 adenovirus was injected into the striatum of mice treated with the neurotoxin MPTP, and dopaminergic neuron survival was quantified by tyrosine hydroxylase immunohistochemistry.
Overexpression of SGK1 reduced reactive oxygen species production, mitigated mitochondrial dysfunction, and rescued neurons from cell death both in vitro and in vivo. Mechanistically, SGK1 achieved these effects by inactivating MKK4, JNK, and GSK3β, which led to decreased ER stress and oxidative stress. The results support the concept that activating SGK1 or modulating its downstream pathways may provide a therapeutic approach to protect neurons in Parkinson’s disease by deactivating harmful JNK and GSK3β signaling cascades.
Paper: “Serum-glucocorticoid-inducible kinase 1 confers protection in cell-based and in vivo neurotoxin models via the c-Jun N-terminal kinase signaling pathway” by Sarah Iqbal, Shannon Howard and Philip V. LoGrasso. Molecular and Cellular Biology. Published online April 15, 2015. doi:10.1128/MCB.01510-14