title: Transduced PEP-1-PON1 proteins regulate microglial activation and dopaminergic neuronal death in a Parkinson's disease model.
abstract: Parkinson's disease (PD) is an oxidative stress-mediated neurodegenerative disorder caused by selective dopaminergic neuronal death in the midbrain substantia nigra. Paraoxonase 1 (PON1) is a potent inhibitor of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) against oxidation by destroying biologically active phospholipids with potential protective effects against oxidative stress-induced inflammatory disorders. In a previous study, we constructed protein transduction domain (PTD) fusion PEP-1-PON1 protein to transduce PON1 into cells and tissue. In this study, we examined the role of transduced PEP-1-PON1 protein in repressing oxidative stress-mediated inflammatory response in microglial BV2 cells after exposure to lipopolysaccharide (LPS). Moreover, we identified the functions of transduced PEP-1-PON1 proteins which include, mitigating mitochondrial damage, decreasing reactive oxidative species (ROS) production, matrix metalloproteinase-9 (MMP-9) expression and protecting against 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity in SH-SY5Y cells. Furthermore, transduced PEP-1-PON1 protein reduced MMP-9 expression and protected against dopaminergic neuronal cell death in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice model. Taken together, these results suggest a promising therapeutic application of PEP-1-PON1 proteins against PD and other inflammation and oxidative stress-related neuronal diseases.
authors.affiliation: Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea.
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea.
authors.forename: Meeyoung
authors.initials: M
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Kangnung-Wonju National University, Gangneung 210-702, Republic of Korea.
authors.forename: Dae Won
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea.
authors.forename: Min Jea
authors.initials: MJ
authors.lastname: Shin
authors.affiliation: Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea.
authors.forename: Ora
authors.initials: O
authors.lastname: Son
authors.affiliation: Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea.
authors.forename: Hyo Sang
authors.initials: HS
authors.lastname: Jo
authors.affiliation: Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea.
authors.forename: Hyeon Ji
authors.initials: HJ
authors.lastname: Yeo
authors.affiliation: Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea.
authors.forename: Su Bin
authors.initials: SB
authors.lastname: Cho
authors.affiliation: Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea.
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea.
authors.forename: Chi Hern
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Anatomy, College of Medicine, Soonchunhyang University, Cheonan-Si 330-090, Republic of Korea.
authors.forename: Duk-Soo
authors.initials: DS
authors.lastname: Kim
authors.affiliation: School of Life Sciences, College of Natural Sciences, Kyungpook National University, Taegu 702-702, Republic of Korea.
authors.forename: Oh-Shin
authors.initials: OS
authors.lastname: Kwon
authors.affiliation: School of Life Science and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Joon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea.
authors.forename: Kyu Hyung
authors.initials: KH
authors.lastname: Han
authors.affiliation: Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea.
authors.forename: Jinseu
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea. Electronic address: wseum@hallym.ac.kr.
authors.forename: Won Sik
authors.initials: WS
authors.lastname: Eum
authors.affiliation: Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea. Electronic address: sychoi@hallym.ac.kr.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D043303:Aryldialkylphosphatase / Q000008:administration & dosage / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000627:therapeutic use*; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D004790:Enzyme Induction / Q000187:drug effects; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D009447:Neuroblastoma / Q000473:pathology; D018384:Oxidative Stress; D020734:Parkinsonian Disorders / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D014161:Transduction, Genetic
chemical_list: D057846:Cell-Penetrating Peptides; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D043303:Aryldialkylphosphatase; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Dopaminergic neuronal death; Inflammation; Oxidative stress; PEP-1-PON1; Parkinson's disease; Protein therapy