Cell-permeable parkin proteins suppress Parkinson disease-associated phenotypes in cultured cells and animals

• Published in: PloS one 2014-07, Vol.9 (7), p.e102517
• Main Authors: Duong, Tam, Kim, Jaetaek, Ruley, H Earl, Jo, Daewoong
• Format: Article
• Language: English
• Subjects: 6-Hydroxydopamine; Animals; Apoptosis; Biocompatibility; Biology and Life Sciences; Cell Line; Cell survival; Cells, Cultured; Chromatography; Corpus Striatum - metabolism; Development and progression; Dopamine; Dopamine - biosynthesis; Dopamine - metabolism; Dopamine receptors; E coli; Etiology; Female; Gene therapy; Genetic aspects; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Hydroxylase; Kinases; Ligases; Medicine; Medicine and Health Sciences; Mesencephalon; Mesencephalon - metabolism; Mice; Mice, Inbred BALB C; Motor Activity; Movement disorders; MPTP; Neostriatum; Neurodegenerative diseases; Neurons; Neurophysiology; Neuroprotection; Neuroprotective Agents - pharmacology; Neurotoxicity; Oxidative stress; Parkin protein; Parkinson disease; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Parkinsons disease; Particulate matter; Permeability; Phenotype; Physical Sciences; Preservation; Proteins; Recombinant Proteins - chemistry; Recombinant Proteins - pharmacology; Rodents; Stress response; Substantia nigra; Survival; Toxicity; Tyrosine; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - metabolism; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - pharmacology; Ubiquitin-Protein Ligases - physiology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0102517

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.