title: Cell-permeable parkin proteins suppress Parkinson disease-associated phenotypes in cultured cells and animals.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder of complex etiology characterized by the selective loss of dopaminergic neurons, particularly in the substantia nigra. Parkin, a tightly regulated E3 ubiquitin ligase, promotes the survival of dopaminergic neurons in both PD and Parkinsonian syndromes induced by acute exposures to neurotoxic agents. The present study assessed the potential of cell-permeable parkin (CP-Parkin) as a neuroprotective agent. Cellular uptake and tissue penetration of recombinant, enzymatically active parkin was markedly enhanced by the addition of a hydrophobic macromolecule transduction domain (MTD). The resulting CP-Parkin proteins (HPM13 and PM10) suppressed dopaminergic neuronal toxicity in cells and mice exposed to 6-hydroxydopamine (6-OHDH) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These included enhanced survival and dopamine expression in cultured CATH.a and SH-SY5Y neuronal cells; and protection against MPTP-induced damage in mice, notably preservation of tyrosine hydroxylase-positive cells with enhanced dopamine expression in the striatum and midbrain, and preservation of gross motor function. These results demonstrate that CP-Parkin proteins can compensate for intrinsic limitations in the parkin response and provide a therapeutic strategy to augment parkin activity in vivo.
authors.affiliation: Department of Biomedical Sciences, Chonnam National University Medical School, Kwangju, Korea.
authors.forename: Tam
authors.initials: T
authors.lastname: Duong
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea.
authors.forename: Jaetaek
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: H Earl
authors.initials: HE
authors.lastname: Ruley
authors.affiliation: Department of Biomedical Sciences, Chonnam National University Medical School, Kwangju, Korea; ProCell R&D Institute, ProCell Therapeutics, Inc., Seoul, Korea.
authors.forename: Daewoong
authors.initials: D
authors.lastname: Jo
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D057927:Hydrophobic and Hydrophilic Interactions; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology
chemical_list: D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine