Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial Parkinsonism associated with mutations in the Parkin gene

Hilker, R.; Klein, Christine; Ghaemi, Mehran; Kis, Bernhard; Strotmann, Tim; Ozelius, Laurie J.; Lenz, Olaf; Vieregge, P.; Herholz, Karl; Heiss, Wolf‐Dieter; Pramstaller, Peter P.

doi:10.1002/ana.74.abs

Cited by 105 publications

(163 citation statements)

References 31 publications

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“…Given that recessive mutations in either of these two genes cause parkinsonism, it is likely that mutations in either parkin or DJ-1 lead to loss of dopaminergic neurons in the substantia nigra that project to the striatum. Positron-emission tomography demonstrates a loss of dopaminergic function in parkin (e.g., [3][4][5][6] and DJ-1 (7,8) patients, supporting this idea. Therefore, although detailed pathology of these two genetic forms of parkinsonism is not available, there are clear phenotypic overlaps.…”

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confidence: 77%

Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability

Beilina

Brug

Ahmad

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

343

322

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Several mutations in PTEN-induced putative kinase 1 (PINK1) gene have been reported to be associated with recessive parkinsonism. The encoded protein is predicted to be a Ser͞Thr protein kinase targeted to mitochondria. In this study, we have investigated the effects of mutations on PINK1 kinase activity in vitro and on expression levels and localization in mammalian cells. We chose to examine two point mutations: G309D, which was originally reported to be stable and properly localized in cells and L347P, which is of interest because it is present at an appreciable carrier frequency in the Philippines. We were able to confirm kinase activity and produce artificial ''kinase-dead'' mutants that are stable but lack activity. The L347P mutation grossly destabilizes PINK1 and drastically reduces kinase activity, whereas G309D has much more modest effects on these parameters in vitro. This finding is in line with predictions based on homology modeling. We also examined the localization of PINK1 in transfected mammalian cells by using constructs that were tagged with myc or GFP at either end of the protein. These results show that PINK1 is processed at the N terminus in a manner consistent with mitochondrial import, but the mature protein also exists in the cytosol. The physiological relevance of this observation is not yet clear, but it implies that a portion of PINK1 may be exported after processing in the mitochondria. mitochondria ͉ PARK6 ͉ Parkinson's disease S everal genes have now been identified that are causally associated with recessive parkinsonism. Mutations in parkin (1) are a relatively frequent cause of parkinsonism with onset before the age of 50, having a varied but generally mild phenotype. DJ-1 mutations are less common than parkin mutations, but the phenotype is broadly similar (2). Given that recessive mutations in either of these two genes cause parkinsonism, it is likely that mutations in either parkin or DJ-1 lead to loss of dopaminergic neurons in the substantia nigra that project to the striatum. Positron-emission tomography demonstrates a loss of dopaminergic function in parkin (e.g., 3-6) and DJ-1 (7, 8) patients, supporting this idea. Therefore, although detailed pathology of these two genetic forms of parkinsonism is not available, there are clear phenotypic overlaps. This conclusion argues that there are relationships between parkin and DJ-1, but the normal functions of the two wild-type proteins are not obviously linked. Parkin is an E3 protein-ubiquitin ligase (9), whereas DJ-1 may have a number of roles (10) but can affect the ability of neurons to survive oxidative stress generated as a result of mitochondrial damage (11).Recently, mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been described that are also associated with recessive parkinsonism. Initially, three pedigrees were described with identified mutations: a G309D point substitution in one family and a truncation mutation (W437X) in two additional families (12). Subsequently, several studies have described co...

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confidence: 77%

Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability

Beilina

Brug

Ahmad

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

343

322

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“…Despite extensive mutational analysis, a considerable percentage of EOP cases have been shown to carry a single heterozygous mutation in the Parkin, DJ-1, and PINK1 gene. 10,14,16,29 -31 In addition, preclinical changes have been detected in asymptomatic carriers of heterozygous Parkin mutations using positron emission tomography (PET) 32,33 or transcranial ultrasound. 34 Interestingly, haploinsufficiency or a dominant-negative effect have been suggested for heterozygous PINK1 mutations even prior to the identification of the PARK6-related gene: asymptomatic, heterozygous carriers of the PARK6-associated haplotype revealed a significant reduction in caudate (18)F-dopa uptake in a PET study in comparison with controls.…”

Section: Discussionmentioning

confidence: 99%

PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism

et al. 2005

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Recessively inherited early-onset parkinsonism (EOP) has been associated with mutations in the Parkin, DJ-1, and PINK1 genes. We studied the prevalence of mutations in all three genes in 65 Italian patients (mean age of onset: 43.275.4 years, 62 sporadic, three familial), selected by age at onset equal or younger than 51 years. Clinical features were compatible with idiopathic Parkinson's disease in all cases. To detect small sequence alterations in Parkin, DJ-1, and PINK1, we performed a conventional mutational analysis (SSCP/ dHPLC/sequencing) of all coding exons of these genes. To test for the presence of exon rearrangements in PINK1, we established a new quantitative duplex PCR assay. Gene dosage alterations in Parkin and DJ-1 were excluded using previously reported protocols. Five patients (8%; one woman/four men; mean age at onset: 38.279.7 (range 25-49) years) carried mutations in one of the genes studied: three cases had novel PINK1 mutations, one of which occurred twice (homozygous c.1602_1603insCAA; heterozygous c.1602_1603insCAA; heterozygous c.836G4A), and two patients had known Parkin mutations (heterozygous c.734A4T and c.924C4T; heterozygous c.924C4T). Family history was negative for all mutation carriers, but one with a history of tremor. Additionally, we detected one novel polymorphism (c.344A4T) and four novel PINK1 changes of unknown pathogenic significance (À21G/A; IVS1 þ 97A/G; IVS3 þ 38_40delTTT; c.852C4T), but no exon rearrangements. No mutations were found in the DJ-1 gene. The number of mutation carriers in both the Parkin and the PINK1 gene in our cohort is low but comparable, suggesting that PINK1 has to be considered in EOP.

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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(Hilker et al, , 2002Oliveira et al, 2003;Khan et al, 2005;L. N. Clark et al, 2006;Sun et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

DrosophilaOverexpressing Parkin R275W Mutant Exhibits Dopaminergic Neuron Degeneration and Mitochondrial Abnormalities

Cheng¹,

Lu²,

Ouyang³

et al. 2007

J. Neurosci.

124

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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 agedependent 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.

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Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial Parkinsonism associated with mutations in the Parkin gene

Cited by 105 publications

References 31 publications

Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability

Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability

PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism

DrosophilaOverexpressing Parkin R275W Mutant Exhibits Dopaminergic Neuron Degeneration and Mitochondrial Abnormalities

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