Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single Parkin mutation

MRC Clinical Sciences Centre, and Division of Neuroscience, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, UK.
Neurology (Impact Factor: 8.29). 02/2005; 64(1):134-6. DOI: 10.1212/01.WNL.0000148725.48740.6D
Source: PubMed


Parkin disease is usually autosomal recessive; however, two studies have shown that asymptomatic heterozygotes have nigrostriatal dysfunction and even manifest subtle extrapyramidal signs. The authors used 18F-dopa PET to study 13 asymptomatic parkin heterozygotes and found a significant reduction of (18)F-dopa uptake in caudate, putamen, ventral, and dorsal midbrain compared with control subjects. Four had subtle extrapyramidal signs. Parkin heterozygosity is a risk factor for nigrostriatal dysfunction and in some may contribute to late-onset Parkinson disease.

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    • "The loss of normal parkin function is an established genetic mechanism in the pathogenesis of early-onset PD but the role of heterozygous parkin mutants as a risk factor for PD remains controversial and requires additional genetic studies (Klein et al., 2007). Multiple lines of evidence, including PET and MRI imaging, transcranial sonography, and clinical exams consistently demonstrate that otherwise asymptomatic heterozygous parkin mutation carriers exhibit significant nigrostriatal dysfunction and mild extrapyramidal motor deficits (Hilker et al., 2001; Varrone et al., 2004; Khan et al., 2005). The genetic mechanism underlying the heterozygous parkin mutation effect on DA neurons remains unclear, but could be due to either a partial loss-of-function (i.e. "
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    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.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 03/2009; 29(7):1962-76. DOI:10.1523/JNEUROSCI.5351-08.2009 · 6.34 Impact Factor
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    • "This is mostly supported by neurophysiological and functional neuroimaging studies, that showed significant albeit subclinical signs of dopaminergic dysfunction in healthy carriers of Parkin and PINK1 single mutations (reviewed in Klein et al., 2007). A role for these variants as PD susceptibility factors would justify their higher frequency among our patients with positive family history of unclear inheritance (6.5%), and their occurrence also in healthy subjects and in individuals with very mild parkinsonian signs (Khan et al., 2005; Hedrich et al., 2006). Yet, it is presently unknown whether the subclinical abnormalities found in healthy heterozygotes are going to remain stable or to evolve towards a clinically manifest phenotype. "
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    ABSTRACT: Heterozygous rare variants in the PINK1 gene, as well as in other genes causing autosomal recessive parkinsonism, have been reported both in patients and healthy controls. Their pathogenic significance is uncertain, but they have been suggested to represent risk factors to develop Parkinson disease (PD). The few large studies that assessed the frequency of PINK1 heterozygotes in cases and controls yielded controversial results, and the phenotypic spectrum is largely unknown. We retrospectively analyzed the occurrence of PINK1 heterozygous rare variants in over 1100 sporadic and familial patients of all onset ages and in 400 controls. Twenty patients and 6 controls were heterozygous, with frequencies (1.8% vs. 1.5%) not significantly different in the two groups. Clinical features of heterozygotes were indistinguishable to those of wild-type patients, with mean disease onset 10 years later than in carriers of two mutations but worse disease progression. A meta-analysis indicated that, in PINK1 heterozygotes, the PD risk is only slightly increased with a non significant odds ratio of 1.62. These findings suggest that PINK1 heterozygous rare variants play only a minor susceptibility role in the context of a multifactorial model of PD. Hence, their significance should be kept distinct from that of homozygous/compound heterozygous mutations, that cause parkinsonism inherited in a mendelian fashion.
    Human Mutation 04/2008; 29(4):565. DOI:10.1002/humu.20719 · 5.14 Impact Factor
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    • "These parkin mutations include exonic deletion , duplication, and triplication as well as several missense/ nonsense substitutions. Although initially described as a recessive disorder, emerging evidence suggest that heterozygous parkin mutations may confer increased susceptibility to PD (Hilker et al., 2001, 2002; Oliveira et al., 2003; Khan et al., 2005; L. N. Clark et al., 2006; Sun et al., 2006). Although parkin haploinsufficiency may explain for the increased risk for PD associated with single parkin mutations, the possibility that some parkin heterozygous mutations may be pathogenic cannot be excluded. "
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    ABSTRACT: Mutations in the parkin gene are a predominant cause of familial parkinsonism. Although initially described as a recessive disorder, emerging evidence suggest that single parkin mutations alone may confer increased susceptibility to Parkinson's disease. To better understand the effects of parkin mutations in vivo, we generated transgenic Drosophila overexpressing two human parkin missense mutants, R275W and G328E. Transgenic flies that overexpress R275W, but not wild-type or G328E, human parkin display an age-dependent degeneration of specific dopaminergic neuronal clusters and concomitant locomotor deficits that accelerate with age or in response to rotenone treatment. Furthermore, R275W mutant flies also exhibit prominent mitochondrial abnormalities in their flight muscles. Interestingly, these defects caused by the expression of human R275W parkin are highly similar to those triggered by the loss of endogenous parkin in parkin null flies. Together, our results provide the first in vivo evidence demonstrating that parkin R275W mutant expression mediates pathogenic outcomes and suggest the interesting possibility that select parkin mutations may directly exert neurotoxicity in vivo.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2007; 27(32):8563-70. DOI:10.1523/JNEUROSCI.0218-07.2007 · 6.34 Impact Factor
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