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

Abstract

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.