title: Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant alpha-synuclein.
abstract: Recessive mutations in parkin are the most common cause of familial early-onset Parkinson's disease (PD). Recent studies suggest that certain parkin mutants may exert dominant toxic effects to cultured cells and such dominant toxicity can lead to progressive dopaminergic (DA) neuron degeneration in Drosophila. To explore whether mutant parkin could exert similar pathogenic effects to mammalian DA neurons in vivo, we developed a BAC (bacterial artificial chromosome) transgenic mouse model expressing a C-terminal truncated human mutant parkin (Parkin-Q311X) in DA neurons driven by a dopamine transporter promoter. Parkin-Q311X mice exhibit multiple late-onset and progressive hypokinetic motor deficits. Stereological analyses reveal that the mutant mice develop age-dependent DA neuron degeneration in substantia nigra accompanied by a significant loss of DA neuron terminals in the striatum. Neurochemical analyses reveal a significant reduction of the striatal dopamine level in mutant mice, which is significantly correlated with their hypokinetic motor deficits. Finally, mutant Parkin-Q311X mice, but not wild-type controls, exhibit age-dependent accumulation of proteinase K-resistant endogenous alpha-synuclein in substantia nigra and colocalized with 3-nitrotyrosine, a marker for oxidative protein damage. Hence, our study provides the first mammalian genetic evidence that dominant toxicity of a parkin mutant is sufficient to elicit age-dependent hypokinetic motor deficits and DA neuron loss in vivo, and uncovers a causal relationship between dominant parkin toxicity and progressive alpha-synuclein accumulation in DA neurons. Our study underscores the need to further explore the putative link between parkin dominant toxicity and PD.
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Lu
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Fleming
authors.forename: Bernhard
authors.initials: B
authors.lastname: Meurers
authors.forename: Larry C
authors.initials: LC
authors.lastname: Ackerson
authors.forename: Farzad
authors.initials: F
authors.lastname: Mortazavi
authors.forename: Victor
authors.initials: V
authors.lastname: Lo
authors.forename: Daniela
authors.initials: D
authors.lastname: Hernandez
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
authors.forename: George R
authors.initials: GR
authors.lastname: Jackson
authors.forename: Nigel T
authors.initials: NT
authors.lastname: Maidment
authors.forename: Marie-Francoise
authors.initials: MF
authors.lastname: Chesselet
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D019286:Endopeptidase K / Q000378:metabolism / Q000494:pharmacology; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017434:Protein Structure, Tertiary / Q000235:genetics; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D019286:Endopeptidase K; D004298:Dopamine