title: Endogenous Parkin Preserves Dopaminergic Substantia Nigral Neurons following Mitochondrial DNA Mutagenic Stress.
abstract: Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. PARK2 mutations cause early-onset forms of PD. PARK2 encodes an E3 ubiquitin ligase, Parkin, that can selectively translocate to dysfunctional mitochondria to promote their removal by autophagy. However, Parkin knockout (KO) mice do not display signs of neurodegeneration. To assess Parkin function in vivo, we utilized a mouse model that accumulates dysfunctional mitochondria caused by an accelerated generation of mtDNA mutations (Mutator mice). In the absence of Parkin, dopaminergic neurons in Mutator mice degenerated causing an L-DOPA reversible motor deficit. Other neuronal populations were unaffected. Phosphorylated ubiquitin was increased in the brains of Mutator mice, indicating PINK1-Parkin activation. Parkin loss caused mitochondrial dysfunction and affected the pathogenicity but not the levels of mtDNA somatic mutations. A systemic loss of Parkin synergizes with mitochondrial dysfunction causing dopaminergic neuron death modeling PD pathogenic processes.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Pickrell
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chiu-Hui
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98104, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Kennedy
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alban
authors.initials: A
authors.lastname: Ordureau
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Dionisia P
authors.initials: DP
authors.lastname: Sideris
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98104, USA.
authors.forename: Jake G
authors.initials: JG
authors.lastname: Hoekstra
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: youle@helix.nih.gov.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D007980:Levodopa / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000235:genetics / Q000473:pathology*; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D040901:Proteomics; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D050483:Dopamine Plasma Membrane Transport Proteins; D009097:Multienzyme Complexes; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein