RING finger 1 mutations in Parkin produce altered localization of the protein

Cookson, Mark; Lockhart, Paul J.; McLendon, Chris; O’Farrell, Casey; Schlossmacher, Michael G.; Farrer, Matthew J.

doi:10.1093/hmg/ddg328

Cited by 145 publications

(116 citation statements)

References 44 publications

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“…24 It was reported to produce an unusual distribution of the Parkin protein, with large cytoplasmic and nuclear inclusions. 26 The rate of PINK1 mutations in EOP is currently largely unknown, but estimated to be almost as high as the frequency of Parkin mutations based on a single study that reported seven PINK1 mutation carriers among 100 EOP patients, including five with heterozygous mutations. 10 Taking a different approach, a second investigation evaluated the role of PINK1 mutations in a set of 39 families with autosomal recessively inherited EOP and detected homozygous PINK1 mutations in six out of the eight EOP families that were shown to be linked to the PINK1 chromosomal region.…”

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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“…Third, although some proposed substrates such as Pael-R accumulate in postmortem AR-JP brains (Imai et al, 2001;Shimura et al, 2001), parkin knock-out mice do not show elevated steady-state concentrations of other substrates such as CDCrel-1 and synphilin-1 (Von Coelln et al, 2004). Fourth, many parkin mutations show altered solubility and form aggresome-like structures in transfected cells (Ardley et al, 2003;Cookson et al, 2003;Gu et al, 2003;Muqit et al, 2004;Henn et al, 2005;Wang et al, 2005a), thereby conferring potentially toxic properties.…”

Section: Relationship Between Parkin Mutations and Cell Deathmentioning

confidence: 99%

ADrosophilaModel of Mutant Human Parkin-Induced Toxicity Demonstrates Selective Loss of Dopaminergic Neurons and Dependence on Cellular Dopamine

Sang¹,

Chang²,

Lawless³

et al. 2007

J. Neurosci.

136

118

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Mutations in human parkin have been identified in familial Parkinson's disease and in some sporadic cases. Here, we report that expression of mutant but not wild-type human parkin in Drosophila causes age-dependent, selective degeneration of dopaminergic (DA) neurons accompanied by a progressive motor impairment. Overexpression or knockdown of the Drosophila vesicular monoamine transporter, which regulates cytosolic DA homeostasis, partially rescues or exacerbates, respectively, the degenerative phenotypes caused by mutant human parkin. These results support a model in which the vulnerability of DA neurons to parkin-induced neurotoxicity results from the interaction of mutant parkin with cytoplasmic dopamine.

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“…Perhaps those types of mutations may contribute to explain the effect of some heterozygous mutations in humans. In fact, missense mutations in both RING fingers of parkin that dramatically alter its cellular localization and generate both cytoplasmic and nuclear inclusions in neuronal cell culture assays have been recently described (12,27).…”

Section: The Rbr Domainmentioning

confidence: 99%

Parkin and relatives: the RBR family of ubiquitin ligases

Marı́n

Lucas

Gradilla

et al. 2004

Physiological Genomics

104

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parkin gene cause autosomal-recessive juvenile parkinsonism. Parkin encodes a ubiquitinprotein ligase characterized by having the RBR domain, composed of two RING fingers plus an IBR/DRIL domain. The RBR family is defined as the group of genes whose products contain an RBR domain. RBR family members exist in all eukaryotic species for which significant sequence data is available, including animals, plants, fungi, and several protists. The integration of comparative genomics with structural and functional data allows us to conclude that RBR proteins have multiple roles, not only in protein quality control mechanisms, but also as indirect regulators of transcription. A recently formulated hypothesis, based on a case of gene fusion, suggested that RBR proteins may be often part of cullin-containing ubiquitin ligase complexes. Recent data on Parkin protein agrees with that hypothesis. We discuss the involvement of RBR proteins in several neurodegenerative diseases and cancer.Parkinson disease; protein quality control; transcriptional regulation THE INTEGRATION OF GENOMIC and proteomic data is providing new perspectives on the origin of genes and the functions of their products. This review is focused on the information generated by the combination of functional and comparative genomic analysis of the RBR gene family. RBR genes are being extensively studied since the discovery that mutations in one of them, named parkin, are a frequent cause of familial autosomal-recessive juvenile parkinsonism (AR-JP). Since then, evidence has been obtained suggesting that RBR proteins are ubiquitin-protein ligases that function as key components of the cellular machinery that controls protein quality. They are also involved in other processes, including regulation of transcription factors such as p53 or the androgen receptor.Although the last years have brought significant advances, our knowledge of RBR protein functions is still extremely fragmentary. One of the main conclusions obtained from the comparative genomic data is that this is an ancient and complex family. Multiple members are present in all eukaryotic species for which we have significant sequence information. The structures of several RBR proteins have diversified by incorporating new protein domains and rare cases of fusions of RBR genes with totally unrelated genes have been found as well. In conclusion, we can expect RBR proteins to play a wide repertoire of functions in all eukaryotic organisms. Much of that diversity has been only superficially explored. The information hitherto available will be summarized here.A final aspect that we discuss in this work is the fact that comparative genomics may be used, in favorable cases, to obtain precise hints of the functions of proteins or even protein families. As we will show below, some of the characteristic features of the RBR proteins, such as their involvement in protein ubiquitination or even their interaction with particular types of proteins to generate ubiquitin-ligase complexes, can be deduced, in absence of any...

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RING finger 1 mutations in Parkin produce altered localization of the protein

Cited by 145 publications

References 44 publications

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

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

ADrosophilaModel of Mutant Human Parkin-Induced Toxicity Demonstrates Selective Loss of Dopaminergic Neurons and Dependence on Cellular Dopamine

Parkin and relatives: the RBR family of ubiquitin ligases

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