title: The serum- and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin.
abstract: Huntington's disease (HD) is caused by abnormal polyglutamine (polyQ) expansion in the protein huntingtin. We have previously demonstrated the importance of the insulin-like growth factor I (IGF-1)/Akt pathway in HD. Indeed, upon IGF-1 activation, Akt phosphorylates polyQ-huntingtin at serine 421 and abrogates its toxicity. In addition, we have demonstrated that Akt is altered in the brain of HD patients. Here, we investigate the role of the serum- and glucocorticoid-induced kinase (SGK) in HD. We show that SGK phosphorylates huntingtin at serine 421 and that phosphorylation can protect striatal neurons against polyQ-huntingtin-induced toxicity. We find that SGK levels are increased in the brain of HD patients. Using a cellular model of HD, we demonstrate that the SGK dysregulation induced by polyQ-huntingtin occurs via the p38/MAPK pathway. Collectively, our results strongly suggest the involvement of SGK in HD and further imply that IGF-1 downstream signalling is a key transduction pathway that regulates the toxicity of huntingtin.
authors.affiliation: UMR 146 CNRS/Institut Curie, Bldg. 110, Centre Universitaire, 91405 Orsay Cedex, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Rangone
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Poizat
authors.forename: Juan
authors.initials: J
authors.lastname: Troncoso
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: Frédéric
authors.initials: F
authors.lastname: Saudou
authors.forename: Sandrine
authors.initials: S
authors.lastname: Humbert
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D017874:Immediate-Early Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D010766:Phosphorylation; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000071058:Huntingtin Protein; D017874:Immediate-Early Proteins; D007334:Insulin-Like Growth Factor I; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D000099184:Serum-Glucocorticoid Regulated Kinases; C086055:HTT protein, human; C499524:Htt protein, rat