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

• Published in: The FEBS journal Vol. 290; no. 11; pp. 2923 - 2938
• Main Authors: Choi, Yeon Joo, Kwon, Hyun Jung, Shin, Min Jea, Kim, Dae Won, Youn, Gi Soo, Park, Jung Hwan, Yeo, Hyeon Ji, Yeo, Eun Ji, Kim, Hyeong Seop, Lee, Lee Re, Kim, Na Yeon, Kwon, Su Yeon, Kim, Duk‐Soo, Kim, Gun Woo, Park, Jinseu, Han, Kyu Hyung, Lee, Keun Wook, Park, Jong Kook, Lee, Chan Hee, Eum, Won Sik, Choi, Soo Young
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-06-2023
• Subjects: Adenosine; Animal models; Apoptosis; BAX protein; Biliverdin; Biliverdin reductase; Blood-brain barrier; Caspase; Cell death; Cytotoxicity; Damage; DNA damage; Dopamine receptors; Fusion protein; GK2‐BLVRA; Kinases; MAP kinase; MAPK; Movement disorders; MPP; MPTP; Neurodegenerative diseases; Oxidative stress; Parkinson's disease; Pharmacology; protein therapy; Proteins; Reactive oxygen species; Reductases; Substantia nigra; Parkinson's disease; protein therapy; MAPK; GK2-BLVRA; oxidative stress
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16721

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.
Here, we developed a novel GK‐2 protein transduction domain that, when fused with BLVARA (GK2‐BLVARA), transduces into cells and markedly protects against oxidative stress‐induced cell death by inhibiting ROS and regulating MAPK pathways. Therefore, the GK2‐BLVARA protein might be a novel therapeutic agent for treating cell death‐induced neurodegenerative diseases.