Involvement of induction and mitochondrial targeting of orphan nuclear receptor Nur77 in 6-OHDA-induced SH-SY5Y cell death

The orphan nuclear receptor Nur77 is a member of the nuclear receptor superfamily. Nur77 is known to regulate survival and death in response to extracellular stimuli, but it is unclear whether Nur77 is regulated by oxidative stress and contributes to the cytotoxicity in neurodegenerative diseases. Here we showed that (1) Nur77 was up-regulated, phosphorylated, and translocated from the nucleus into the cytosol and mitochondria by H2O2 treatment in HEK293 cells, as well as in 6-hydroxy dopamine (6-OHDA)-treated dopaminergic SH-SY5Y cells, (2) oxidative stress-mediated cell death was exacerbated in Nur77-overexpressed cells and abolished by dominant-negative-Nur77 transfection, and (3) blockade of nuclear export attenuated 6-OHDA-induced SH-SY5Y cell death. Together, our results show that the nuclear export and targeting to mitochondria of Nur77 and resultant activation of apoptotic death may participate in the pathogenesis of Parkinson's disease.