title: Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway.
abstract: 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 c-Jun N-terminal kinase (JNK) signaling and endoplasmic reticulum (ER) stress induced by 6-hydroxydopamine. SGK1-expressing adenovirus was created and used to overexpress SGK1 in SH-SY5Y 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 overexpression in vivo, SGK1-expressing adenovirus was injected into the striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and protection of dopaminergic neurons was quantitatively assessed by tyrosine hydroxylase immunohistochemistry. SGK1 overexpression was found to decrease reactive oxygen species generation, alleviate mitochondrial dysfunction, and rescue cell death in vitro and in vivo by inactivating mitogen-activated protein kinase kinase 4 (MKK4), JNK, and glycogen synthase kinase 3β (GSK3β) and thereby decreasing ER and oxidative stress. These results suggest that therapeutic strategies for activation of SGK1 may have the potential to be neuroprotective by deactivating the JNK and GSK3β pathways.
authors.affiliation: Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Iqbal
authors.affiliation: Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Howard
authors.affiliation: Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Jupiter, Florida, USA lograsso@scripps.edu.
authors.forename: Philip V
authors.initials: PV
authors.lastname: LoGrasso
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D016627:Oxidopamine / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017874:Immediate-Early Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016627:Oxidopamine; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D000099184:Serum-Glucocorticoid Regulated Kinases; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse
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