Increased Risk for Heterozygotes in Recessive Parkinson Disease

Beffert, Uwe; Rosenberg, Roger N.

doi:10.1001/archneur.63.6.807

Cited by 3 publications

(1 citation statement)

References 12 publications

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“…These studies suggest that heterozygous parkin mutations may manifest as clinically asymptomatic DA neuron dysfunction and degeneration or as sporadic cases of early-onset PD (West et al, 2002; Foroud et al, 2003; Beffert and Rosenberg, 2006; Clark et al, 2006b; Sun et al, 2006). However, data derived from the human genetic studies are suggestive but not conclusive on this issue (Lincoln et al, 2003; Khan et al, 2005; Clark et al, 2006a; Lesage et al, 2007).…”

Section: Discussionmentioning

confidence: 97%

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 α-Synuclein

Lu¹,

Fleming²,

Meurers³

et al. 2009

J. Neurosci.

169

130

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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 ␣-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 agedependent hypokinetic motor deficits and DA neuron loss in vivo, and uncovers a causal relationship between dominant parkin toxicity and progressive ␣-synuclein accumulation in DA neurons. Our study underscores the need to further explore the putative link between parkin dominant toxicity and PD.

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