Protective effect of GK2 fused BLVRA protein against oxidative stress-induced dopaminergic neuronal cell damage

It is well known that oxidative stress is highly associated with Parkinson's disease (PD), and biliverdin reductase A (BLVRA) is known to have antioxidant properties against oxidative stress. In this study, we developed a novel N-acetylgalactosamine kinase (GK2) protein transduction domain (PTD) derived from adenosine A2A and fused with BLVRA to determine whether the GK2-BLVRA fusion protein could protect dopaminergic neuronal cells (SH-SY5Y) from oxidative stress in vitro and in vivo using a PD animal model. GK2-BLVRA was transduced into various cells, including SH-SY5Y cells, without cytotoxic effects, and this fusion protein protected SH-SY5Y cells and reduced reactive oxygen species production and DNA damage after 1-methyl-4-phenylpyridinium (MPP+) exposure. GK2-BLVRA suppressed mitogen-activated protein kinase (MAPK) activation and modulated apoptosis-related protein (Bcl-2, Bax, cleaved Caspase-3 and -9) expression levels. In the PD animal model, GK2-BLVRA transduced into the substantia nigra crossed the blood-brain barrier and markedly reduced dopaminergic neuronal cell death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animals. These results indicate that our novel PTD GK-2 is useful for the transduction of protein, and GK2-BLVRA exhibits a beneficial effect against dopaminergic neuronal cell death in vitro and in vivo, suggesting that BLVRA can be used as a therapeutic agent for PD.