The serum- and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin.
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.
Rangone
Hélène
H
UMR 146 CNRS/Institut Curie, Bldg. 110, Centre Universitaire, 91405 Orsay Cedex, France.
Poizat
Ghislaine
G
Troncoso
Juan
J
Ross
Christopher A
CA
MacDonald
Marcy E
ME
Saudou
Frédéric
F
Humbert
Sandrine
S
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
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