Serum and glucocorticoid-regulated kinase 1 (sgk1) belongs to a family of serine/threonine kinases that is under acute transcriptional control by serum and glucocorticoids. An expanding set of receptors and cellular stress pathways has been shown to enhance sgk1 expression, which is implicated in the regulation of ion channel conductance, cell volume, cell cycle progression, and apoptosis. Recent evidence for the involvement of sgk1 in the early pathogenesis of MPTP-induced Parkinson's disease (PD) prompted us to investigate in more detail its expression and role in animal models of different neurodegenerative diseases. Here, we show that transcription of sgk1 is increased in several animal models of PD and a transgenic model of amyotrophic lateral sclerosis (ALS). The upregulation of sgk1 strongly correlates with the occurrence of cell death. Furthermore, we provide evidence that the Forkhead transcription factor FKHRL1 and some of the voltage-gated potassium channels are physiological substrates of sgk1 in vivo. Using a small interfering RNA approach to silence sgk1 transcripts in vitro, we give evidence that sgk1 exerts a protective role in oxidative stress situations. These findings underline a key role for sgk1 in the molecular pathway of cell death, in which sgk1 seems to exert a protective role.