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.

TitleBacterial 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.
Publication TypeJournal Article
Year of Publication2009
AuthorsLu, X-H, Fleming SM, Meurers B, Ackerson LC, Mortazavi F, Lo V, Hernandez D, Sulzer D, Jackson GR, Maidment NT, Chesselet M-F, Yang WX
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience
Volume29
Issue7
Pagination1962-76
Date Published2009 Feb 18
ISSN1529-2401
KeywordsAging, alpha-Synuclein, Animals, Chromosomes, Artificial, Bacterial, Corpus Striatum, Disease Models, Animal, Dopamine, Endopeptidase K, Genetic Vectors, Humans, Mice, Mice, Transgenic, Movement Disorders, Mutation, Nerve Degeneration, Parkinson Disease, Protein Structure, Tertiary, substantia nigra, Transfection, Ubiquitin-Protein Ligases
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.

DOI10.1111/j.1553-2712.2011.01024.x
Alternate JournalJ. Neurosci.