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      PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy

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          Abstract

          Defective mitochondrial quality control is shown to be a mechanism for neurodegeneration in some forms of Parkinson's disease.

          Abstract

          Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Recent identification of genes linked to familial forms of PD such as Parkin and PINK1 ( PTEN-induced putative kinase 1) has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. However, the exact mechanism underlying the functional interplay between Parkin-catalyzed ubiquitylation and PINK1-regulated mitochondrial quality control remains an enigma. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential–dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. Interestingly, the ubiquitin ligase activity of Parkin is repressed in the cytoplasm under steady-state conditions; however, PINK1-dependent mitochondrial localization liberates the latent enzymatic activity of Parkin. Some pathogenic mutations of PINK1 and Parkin interfere with the aforementioned events, suggesting an etiological importance. These results provide crucial insight into the pathogenic mechanisms of PD.

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          Most cited references18

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          Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin.

          Mutations in Pink1, a gene encoding a Ser/Thr kinase with a mitochondrial-targeting signal, are associated with Parkinson's disease (PD), the most common movement disorder characterized by selective loss of dopaminergic neurons. The mechanism by which loss of Pink1 leads to neurodegeneration is not understood. Here we show that inhibition of Drosophila Pink1 (dPink1) function results in energy depletion, shortened lifespan, and degeneration of select indirect flight muscles and dopaminergic neurons. The muscle pathology was preceded by mitochondrial enlargement and disintegration. These phenotypes could be rescued by the wild type but not the pathogenic C-terminal deleted form of human Pink1 (hPink1). The muscle and dopaminergic phenotypes associated with dPink1 inactivation show similarity to that seen in parkin mutant flies and could be suppressed by the overexpression of Parkin but not DJ-1. Consistent with the genetic rescue results, we find that, in dPink1 RNA interference (RNAi) animals, the level of Parkin protein is significantly reduced. Together, these results implicate Pink1 and Parkin in a common pathway that regulates mitochondrial physiology and cell survival in Drosophila.
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            Retrovirus-mediated gene transfer and expression cloning: powerful tools in functional genomics.

            Most of the human genome has now been sequenced and about 30,000 potential open reading frames have been identified, indicating that we use these 30,000 genes to functionally organize our biologic activities. However, functions of many genes are still unknown despite intensive efforts using bioinformatics as well as transgenic and knockout mice. Retrovirus-mediated gene transfer is a powerful tool that can be used to understand gene functions. We have developed a variety of retrovirus vectors and efficient packaging cell lines that have facilitated the development of efficient functional expression cloning methods. In this review, we describe retrovirus-mediated strategies used for investigation of gene functions and function-based screening strategies.
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              Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1.

              Parkinson's disease is a common neurodegenerative disorder in which familial-linked genes have provided novel insights into the pathogenesis of this disorder. Mutations in Parkin, a ring-finger-containing protein of unknown function, are implicated in the pathogenesis of autosomal recessive familial Parkinson's disease. Here, we show that Parkin binds to the E2 ubiquitin-conjugating human enzyme 8 (UbcH8) through its C-terminal ring-finger. Parkin has ubiquitin-protein ligase activity in the presence of UbcH8. Parkin also ubiquitinates itself and promotes its own degradation. We also identify and show that the synaptic vesicle-associated protein, CDCrel-1, interacts with Parkin through its ring-finger domains. Furthermore, Parkin ubiquitinates and promotes the degradation of CDCrel-1. Familial-linked mutations disrupt the ubiquitin-protein ligase function of Parkin and impair Parkin and CDCrel-1 degradation. These results suggest that Parkin functions as an E3 ubiquitin-protein ligase through its ring domains and that it may control protein levels via ubiquitination. The loss of Parkin's ubiquitin-protein ligase function in familial-linked mutations suggests that this may be the cause of familial autosomal recessive Parkinson's disease.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                19 April 2010
                : 189
                : 2
                : 211-221
                Affiliations
                [1 ]Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan
                [2 ]Department of Neurology and [3 ]Research Institute for Diseases of Old Age, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
                [4 ]Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
                [5 ]Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
                Author notes
                Correspondence to Noriyuki Matsuda: matsuda-nr@ 123456igakuken.or.jp ; or Keiji Tanaka: tanaka-kj@ 123456igakuken.or.jp
                Article
                200910140
                10.1083/jcb.200910140
                2856912
                20404107
                7d92b7ae-0abf-48a9-b8db-608c75180aad
                © 2010 Matsuda et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 26 October 2009
                : 22 March 2010
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                Cell biology
                Cell biology

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