Molecular genetic analysis of a novel <i>Parkin</i> gene in Japanese families with autosomal recessive juvenile parkinsonism: Evidence for variable homozygous deletions in the <i>Parkin</i> gene in affected individuals

Hattori, Nobutaka; Kitada, Tohru; Matsumine, Hiroto; Asakawa, Shuichi; Yamamura, Yuichi; Yoshino, Hideaki; Kobayashi, Tomonori; Yokochi, Masayuki; Wang, Mei; Yoritaka, Asako; Kondo, Tomoyoshi; Kuzuhara, Shigeki; Nakamura, Shotaro; Shimizu, Nobuyoshi; Mizuno, Yoshikuni

doi:10.1002/ana.410440612

Cited by 281 publications

(149 citation statements)

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“…Growing evidence indicates that the malfunction of the ubiquitin/proteasome system is closely associated with development of a range of neurodegenerative diseases including PD (26,28). Recently, deletion or point mutations in a member of the ubiquitin protein ligase family (Parkin) were found to be associated with young onset PD, where nigral pathology is not usually associated with Lewy body formation, in several families in Japan, Germany, Turkey, and Yemen (7)(8)(9)(10)(11)(12)(13)(14). Although the mechanism by which mutations in Parkin cause nigral degeneration is not clear, accumulation of abnormal proteins (ubiquitinated or non-ubiquitinated) may directly cause cell death (25,27) and/or may render cells sensitive to death caused by mechanisms such as oxidative stress (18,52).…”

Section: Discussionmentioning

confidence: 99%

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Effect of Wild-type or Mutant Parkin on Oxidative Damage, Nitric Oxide, Antioxidant Defenses, and the Proteasome

Hyun¹,

Lee²,

Hattori³

et al. 2002

Journal of Biological Chemistry

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164

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Mutations in Parkin (a ubiquitin protein ligase) are involved in autosomal recessive juvenile parkinsonism, but it is not known how they cause nigral cell death. We examined the effect of Parkin overexpression on cellular levels of oxidative damage, antioxidant defenses, nitric oxide production, and proteasomal enzyme activity. Increasing expression of Parkin by gene transfection in NT-2 and SK-N-MC cells led to increased proteasomal activity, decreased levels of protein carbonyls, 3-nitrotyrosine-containing proteins, and a trend to a reduction in ubiquitinated protein levels. Transfection of these cells with DNA encoding three mutant Parkins associated with autosomal recessive juvenile parkinsonism (Del 3-5, T240R, and Q311X) gave smaller increases in proteasomal activity and led to elevated levels of protein carbonyls and lipid peroxidation. Turnover of the mutant proteins was slower than that of the wild-type protein, and both could be blocked by the proteasome inhibitor, lactacystin. A rise in levels of nitrated proteins and increased levels of NO 2 ؊ /NO 3 ؊ was also observed in cells transfected with mutant Parkins, apparently because of increased levels of neuronal nitricoxide synthase. The presence of mutant Parkin in substantia nigra in juvenile parkinsonism may increase oxidative stress and nitric oxide production, sensitizing cells to death induced by other insults. Parkinson's disease (PD)1 results from degeneration of dopaminergic neurones in the substantia nigra (1). Although most cases appear sporadic and of unknown cause, oxidative stress and apoptosis are associated with disease progression (1). Consistent with this view, increased levels of oxidative damage to DNA, proteins, and lipids and decreased levels of GSH are found in substantia nigra in PD (1-5).Autosomal recessive juvenile parkinsonism (AR-JP), an early onset form of PD, is characterized by loss of tyrosine hydroxylase-immunoreactive neurones in substantia nigra pars compacta and locus ceruleus, usually without Lewy body formation (6). Various mutations (including deletion or point mutations) in the Parkin gene located on chromosome 6 (6q25.2-q27) have been found in AR-JP patients, but no clear correlations exist between types of Parkin mutations and clinical or pathologic features (7-14).Parkin has been identified as a ubiquitin-protein ligase containing 465 amino acids, which consists of a ubiquitin-like (UBL) domain in the N terminus, two ring-finger motifs (termed RING1 and RING2) flanking a Cys-rich domain, named as the in-between RING (IBR) (9, 14). An additional segment is a linker region that connects two regions of UBL and RING1-IBR-RING2 (named as the RING box). Deletional analysis of Parkin revealed that UBL and the linker region are not necessary for association with a specific E2 enzyme. In contrast, the full region of the RING box is necessary for noncovalent association with E2. Therefore, missense mutations in the RING box of Parkin in AR-JP patients have almost completely lost the specific E2-binding activity.2 Thus, ...

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Section: Discussionmentioning

confidence: 99%

“…Various mutations (including deletion or point mutations) in the Parkin gene located on chromosome 6 (6q25.2-q27) have been found in AR-JP patients, but no clear correlations exist between types of Parkin mutations and clinical or pathologic features (7)(8)(9)(10)(11)(12)(13)(14).…”

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confidence: 99%

Effect of Wild-type or Mutant Parkin on Oxidative Damage, Nitric Oxide, Antioxidant Defenses, and the Proteasome

Hyun¹,

Lee²,

Hattori³

et al. 2002

Journal of Biological Chemistry

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164

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“…MPTP, and its active metabolite MPP ϩ , are also thought to induce oxidative stress in addition to inhibiting mitochondrial function (17). The discovery that mutations in ␣-synuclein (2, 3), parkin, and UCH-L1 (5,9,43,44) are associated with PD led to the recognition that impaired protein degradation is also an important factor in this disorder. Mechanistically, however, it is still unclear what the common thread is among these seemingly disparate cellular responses.…”

Section: -Ohda But Not Mpp ϩ Induces Components Of the Upr Pathwamentioning

confidence: 99%

Parkinsonian Mimetics Induce Aspects of Unfolded Protein Response in Death of Dopaminergic Neurons

Holtz

O’Malley

2003

Journal of Biological Chemistry

346

257

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Genes associated with Parkinson's disease (PD) have suggested a role for ubiquitin-proteasome dysfunction and aberrant protein degradation in this disorder. Inasmuch as oxidative stress has also been implicated in PD, the present study examined transcriptional changes mediated by the Parkinsonism-inducing neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP ؉ ) in a dopaminergic cell line. Microarray analysis of RNA isolated from toxin treated samples revealed that the stress-induced transcription factor CHOP/Gadd153 was dramatically up-regulated by both 6-OHDA and MPP ؉ . Treatment with 6-OHDA also induced a large number of genes involved in endoplasmic reticulum stress and unfolded protein response (UPR) such as ER chaperones and elements of the ubiquitinproteasome system. Reverse transcription-PCR, Western blotting, and immunocytochemical approaches were used to quantify and temporally order the UPR pathways involved in neurotoxin-induced cell death. 6-OHDA, but not MPP ؉ , significantly increased hallmarks of UPR such as BiP, c-Jun, and processed Xbp1 mRNA. Both toxins increased the phosphorylation of UPR proteins, PERK and eIF2␣, but only 6-OHDA increased phosphorylation of c-Jun. Thus, 6-OHDA is capable of triggering multiple pathways associated with UPR, whereas MPP ؉ exhibits a more restricted response. The involvement of UPR in these widely used neurotoxin models supports the role of ubiquitin-proteasome pathway dysfunction in PD.

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“…Hedrich et al (2001) used real-time PCR to determine the gene dosage ratio of the Parkin gene as compared to the reference gene beta globin (HBB) in order to identify heterozygous deletions and/or duplica- Primers used in a study by Hattori et al (1998). b Primers used in a study by Denison et al (2003) Alterations in the common fragile site SR Denison et al tions of whole exons of Parkin in a subset of ARJP patients.…”

Section: Heterozygous Duplication/deletion (Hd) Screeningmentioning

confidence: 99%

Alterations in the common fragile site gene Parkin in ovarian and other cancers

et al. 2003

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The cloning and characterization of the common fragile site (CFS) FRA6E (6q26) identified Parkin, the gene involved in the pathogenesis of many cases of juvenile, early-onset and, rarely, late-onset Parkinson's disease, as the third large gene to be localized within a large CFS. Initial analyses of Parkin indicated that in addition to playing a role in Parkinson's disease, it might also be involved in the development and/or progression of ovarian cancer. These analyses also indicated striking similarities among the large CFS-locus genes: fragile histidine triad gene (FHIT; 3p14.2), WW domain-containing oxidoreductase gene (WWOX; 16q23), and Parkin (6q26). Analyses of FHIT and WWOX in a variety of different cancer types have identified the presence of alternative transcripts with whole exon deletions. Interestingly, various whole exon duplications and deletions have been identified for Parkin in juvenile and early-onset Parkinson's patients. Therefore, we performed mutational/exon rearrangement analysis of Parkin in ovarian cancer cell lines and primary tumors. Four (66.7%) cell lines and four (18.2%) primary tumors were identified as being heterozygous for the duplication or deletion of a Parkin exon. Additionally, three of 23 (13.0%) nonovarian tumorderived cell lines were also identified as having a duplication or deletion of one or more Parkin exons. Analysis of Parkin protein expression with antibodies revealed that most of the ovarian cancer cell lines and primary tumors had diminished or absent Parkin expression. While functional analyses have not yet been performed for Parkin, these data suggest that like FHIT and WWOX, Parkin may represent a tumor suppressor gene.

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Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: Evidence for variable homozygous deletions in the Parkin gene in affected individuals

Cited by 281 publications

References 13 publications

Effect of Wild-type or Mutant Parkin on Oxidative Damage, Nitric Oxide, Antioxidant Defenses, and the Proteasome

Effect of Wild-type or Mutant Parkin on Oxidative Damage, Nitric Oxide, Antioxidant Defenses, and the Proteasome

Parkinsonian Mimetics Induce Aspects of Unfolded Protein Response in Death of Dopaminergic Neurons

Alterations in the common fragile site gene Parkin in ovarian and other cancers

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