Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism

Kitada, Tohru; Asakawa, Shuichi; Hattori, Nobutaka; Matsumine, Hiroto; Yamamura, Yuichi; Minoshima, Shinsei; Yokochi, Masayuki; Mizuno, Yoshikuni; Shimizu, Nobuyoshi

doi:10.1038/33416

Cited by 4,653 publications

(3,319 citation statements)

References 20 publications

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“…Direct sequencing of the complete coding region and the exon/intron boundaries of the candidate genes POLG, 3 POLG2, 4 C10orf2 (Twinkle),5 SLC25A4 (ANT1),7 OPA1, 17 PINK1, 29 and PARK2 30 were carried out as previously described. Large gene deletions or duplications in PARK2 and PINK1 genes were tested by using the MLPA assay for Parkinson disease (SALSA MLPA Kit P051/P052 Parkinson; MRC‐Holland, Amsterdam, the Netherlands).…”

Section: Methodsmentioning

confidence: 99%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

160

106

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ObjectiveMounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.MethodsPatients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements.ResultsAffected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase‐negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy.InterpretationThe association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism. Ann Neurol 2015;78:21–38

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Section: Methodsmentioning

confidence: 99%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

160

106

View full text Add to dashboard Cite

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“…In particular, mutations in the genes for PARK2 and PARK6 give rise to early‐onset or autosomal recessive juvenile parkinsonism (ARJP) forms of the disease that have similar symptoms including rigidity, bradykinesia and postural instability (Jankovic, 2008) but affect individuals at a much younger age. PARK2 encodes the E3 ubiquitin ligase parkin (Kitada et al , 1998) where mutations account for 50% of all ARJP cases. Along with the PTEN‐induced kinase (PINK1) translated from PARK6 , these proteins use the ubiquitin degradation pathway to turnover damaged mitochondria and maintain mitochondrial homeostasis, especially under conditions of oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation

et al. 2018

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The E3 ligase parkin ubiquitinates outer mitochondrial membrane proteins during oxidative stress and is linked to early‐onset Parkinson's disease. Parkin is autoinhibited but is activated by the kinase PINK1 that phosphorylates ubiquitin leading to parkin recruitment, and stimulates phosphorylation of parkin's N‐terminal ubiquitin‐like (pUbl) domain. How these events alter the structure of parkin to allow recruitment of an E2~Ub conjugate and enhanced ubiquitination is an unresolved question. We present a model of an E2~Ub conjugate bound to the phospho‐ubiquitin‐loaded C‐terminus of parkin, derived from NMR chemical shift perturbation experiments. We show the UbcH7~Ub conjugate binds in the open state whereby conjugated ubiquitin binds to the RING1/IBR interface. Further, NMR and mass spectrometry experiments indicate the RING0/RING2 interface is re‐modelled, remote from the E2 binding site, and this alters the reactivity of the RING2(Rcat) catalytic cysteine, needed for ubiquitin transfer. Our experiments provide evidence that parkin phosphorylation and E2~Ub recruitment act synergistically to enhance a weak interaction of the pUbl domain with the RING0 domain and rearrange the location of the RING2(Rcat) domain to drive parkin activity.

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“…The identification of rare highly penetrant mutations in genes causing familial and early onset Parkinson disease (PD)1, 2, 3, 4, 5 has considerably improved our understanding of disease pathogenesis. Recently, our understanding of idiopathic PD has been enhanced by genome‐wide association (GWA) studies6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 that have collectively identified PD risk variants at >18 loci 6, 7.…”

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confidence: 99%

Polygenic risk of Parkinson disease is correlated with disease age at onset

Escott‐Price¹,

Nalls

Morris

et al. 2015

Annals of Neurology

122

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ObjectiveWe have investigated the polygenic architecture of Parkinson disease (PD) and have also explored the potential relationship between an individual's polygenic risk score and their disease age at onset.MethodsThis study used genotypic data from 4,294 cases and 10,340 controls obtained from the meta‐analysis of PD genome‐wide association studies. Polygenic score analysis was performed as previously described by the International Schizophrenia Consortium, testing whether the polygenic score alleles identified in 1 association study were significantly enriched in the cases relative to the controls of 3 independent studies. Linear regression was used to investigate the relationship between an individual's polygenic score for PD risk alleles and disease age at onset.ResultsOur polygenic score analysis has identified significant evidence for a polygenic component enriched in the cases of each of 3 independent PD genome‐wide association cohorts (minimum p = 3.76 × 10−6). Further analysis identified compelling evidence that the average polygenic score in patients with an early disease age at onset was significantly higher than in those with a late age at onset (p = 0.00014).InterpretationThis provides strong support for a large polygenic contribution to the overall heritable risk of PD and also suggests that early onset forms of the illness are not exclusively caused by highly penetrant Mendelian mutations, but can also be contributed to by an accumulation of common polygenic alleles with relatively low effect sizes. Ann Neurol 2015;77:582–591

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Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism

Cited by 4,653 publications

References 20 publications

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation

Polygenic risk of Parkinson disease is correlated with disease age at onset

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