Novel <i>PINK1</i> mutations in early‐onset parkinsonism

Hatano, Yasuko; Li, Yuanzhe; Sato, Kenichi; Asakawa, Shuichi; Yamamura, Yuichi; Tomiyama, Hiroyuki; Yoshino, Hideaki; Asahina, Masato; Kobayashi, Susumu; Hassin‐Baer, Sharon; Lu, Chin‐Song; Ng, Arlene R.; Rosales, Raymond L.; Shimizu, Nobuyoshi; Toda, Tatsushi; Mizuno, Yoshikuni; Hattori, Nobutaka

doi:10.1002/ana.20251

Cited by 252 publications

(174 citation statements)

References 7 publications

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“…More than 50 mutations in the PINK1 gene (1p36), located at the PARK6 locus, have been identified in PD-affected patients [239][240][241][242][243] and these mutations are believed to account for up to 1-8 % of sporadic cases with early onset [244].…”

Section: Pink1 (Park6)mentioning

confidence: 99%

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Grand

Gonzalez-Cano

Pavlou

et al. 2014

Cell. Mol. Life Sci.

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Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, nonmotor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/bcatenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PDrelated genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.

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Section: Pink1 (Park6)mentioning

confidence: 99%

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Grand

Gonzalez-Cano

Pavlou

et al. 2014

Cell. Mol. Life Sci.

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“…PINK1 mutants remain diffusely distributed and are not recruited to mitochondria, resulting in reduced mitochondrial elimination PD-associated mutations in PINK1 have been found in both the kinase and C-terminal domains [2,16]. Among these mutations, G309D, L347P, and G409V are expected to cause a reduction in the kinase activity of PINK1 [13,14,17].…”

Section: Mitochondrial Elimination Is Accomplished By Overexpression mentioning

confidence: 99%

PINK1 is recruited to mitochondria with parkin and associates with LC3 in mitophagy

et al. 2010

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Edited by Jesus AvilaKeywords: PTEN-induced putative kinase 1 Parkin Mitophagy Autophagy Parkinson's disease a b s t r a c t Mutations in PTEN-induced putative kinase 1 (PINK1) cause recessive form of Parkinson's disease (PD). PINK1 acts upstream of parkin, regulating mitochondrial integrity and functions. Here, we show that PINK1 in combination with parkin results in the perinuclear mitochondrial aggregation followed by their elimination. This elimination is reduced in cells expressing PINK1 mutants with wild-type parkin. Although wild-type PINK1 localizes in aggregated mitochondria, PINK1 mutants localization remains diffuse and mitochondrial elimination is not observed. This phenomenon is not observed in autophagy-deficient cells. These results suggest that mitophagy controlled by the PINK1/parkin pathway might be associated with PD pathogenesis. Structured summary:MINT-7557195: PINK1 (uniprotkb:Q9BXM7) physically interacts (MI:0915) with LC3 (uniprotkb:Q9GZQ8) by anti tag coimmunoprecipitation (MI:0007) MINT-7557109: LC3 (uniprotkb:Q9GZQ8) and PINK1

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“…More recent studies have suggested a role for this motif in kinase regulation (27), because variations within this loop appear to favor alternative modes of C-helix positioning (21,28). Mutations at this site produce severe (29,30) and/or dominant-negative effects (31).…”

Section: N-lobementioning

confidence: 99%

Congenital disease SNPs target lineage specific structural elements in protein kinases

Torkamani

Kannan²,

Taylor

et al. 2008

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

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The catalytic domain of protein kinases harbors a large number of disease-causing single nucleotide polymorphisms (SNPs) and common or neutral SNPs that are not known or hypothesized to be associated with any disease. Distinguishing these two types of polymorphisms is critical in accurately predicting the causative role of SNPs in both candidate gene and genome-wide association studies. In this study, we have analyzed the structural location of common and disease-associated SNPs in the catalytic domain of protein kinases and find that, although common SNPs are randomly distributed within the catalytic core, known disease SNPs consistently map to regulatory and substrate binding regions. In particular, a buried side-chain network that anchors the flexible activation loop to the catalytic core is frequently mutated in disease patients. This network was recently shown to be absent in distantly related eukaryotic-like kinases, which lack an exaggerated activation loop and, presumably, are not regulated by phosphorylation.allostery ͉ cancer ͉ conservation ͉ evolution ͉ mutation

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Novel PINK1 mutations in early‐onset parkinsonism

Cited by 252 publications

References 7 publications

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

PINK1 is recruited to mitochondria with parkin and associates with LC3 in mitophagy

Congenital disease SNPs target lineage specific structural elements in protein kinases

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