For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
8
views
47
references
 Top references
cited by
13
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      28
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Aberrant mitochondrial dynamics contribute to disease conditions. Genetic and pharmacological inhibition of USP8 ameliorates mitochondrial phenotypes deriving from loss of function of Drosophila PINK1 and Parkin.

          Abstract

          Aberrant mitochondrial dynamics disrupts mitochondrial function and contributes to disease conditions. A targeted RNA interference screen for deubiquitinating enzymes (DUBs) affecting protein levels of multifunctional mitochondrial fusion protein Mitofusin (MFN) identified USP8 prominently influencing MFN levels. Genetic and pharmacological inhibition of USP8 normalized the elevated MFN protein levels observed in PINK1 and Parkin-deficient models. This correlated with improved mitochondrial function, locomotor performance and life span, and prevented dopaminergic neurons loss in Drosophila PINK1 KO flies. We identified a novel target antagonizing pathologically elevated MFN levels, mitochondrial dysfunction, and dopaminergic neuron loss of a Drosophila model of mitochondrial dysfunction.

          Related collections

          Most cited references47

          • Record: found
          • Abstract: found
          • Article: not found

          Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants.

          Jessica C Greene, Alexander J. Whitworth, Isabella J Kuo … (2003)
          Parkinson's disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. Several lines of evidence strongly implicate mitochondrial dysfunction as a major causative factor in PD, although the molecular mechanisms responsible for mitochondrial dysfunction are poorly understood. Recently, loss-of-function mutations in the parkin gene, which encodes a ubiquitin-protein ligase, were found to underlie a familial form of PD known as autosomal recessive juvenile parkinsonism (AR-JP). To gain insight into the molecular mechanism responsible for selective cell death in AR-JP, we have created a Drosophila model of this disorder. Drosophila parkin null mutants exhibit reduced lifespan, locomotor defects, and male sterility. The locomotor defects derive from apoptotic cell death of muscle subsets, whereas the male sterile phenotype derives from a spermatid individualization defect at a late stage of spermatogenesis. Mitochondrial pathology is the earliest manifestation of muscle degeneration and a prominent characteristic of individualizing spermatids in parkin mutants. These results indicate that the tissue-specific phenotypes observed in Drosophila parkin mutants result from mitochondrial dysfunction and raise the possibility that similar mitochondrial impairment triggers the selective cell loss observed in AR-JP.
          Article 0 comments Cited 384 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy.

            Baris Bingol, Joy S Tea, Lilian Phu … (2014)
            Cells maintain healthy mitochondria by degrading damaged mitochondria through mitophagy; defective mitophagy is linked to Parkinson's disease. Here we report that USP30, a deubiquitinase localized to mitochondria, antagonizes mitophagy driven by the ubiquitin ligase parkin (also known as PARK2) and protein kinase PINK1, which are encoded by two genes associated with Parkinson's disease. Parkin ubiquitinates and tags damaged mitochondria for clearance. Overexpression of USP30 removes ubiquitin attached by parkin onto damaged mitochondria and blocks parkin's ability to drive mitophagy, whereas reducing USP30 activity enhances mitochondrial degradation in neurons. Global ubiquitination site profiling identified multiple mitochondrial substrates oppositely regulated by parkin and USP30. Knockdown of USP30 rescues the defective mitophagy caused by pathogenic mutations in parkin and improves mitochondrial integrity in parkin- or PINK1-deficient flies. Knockdown of USP30 in dopaminergic neurons protects flies against paraquat toxicity in vivo, ameliorating defects in dopamine levels, motor function and organismal survival. Thus USP30 inhibition is potentially beneficial for Parkinson's disease by promoting mitochondrial clearance and quality control.
            Article 0 comments Cited 326 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control.

              Gian-Luca McLelland, Vincent Soubannier, Carol X.-Q. Chen … (2014)
              Mitochondrial dysfunction has long been associated with Parkinson's disease (PD). Parkin and PINK1, two genes associated with familial PD, have been implicated in the degradation of depolarized mitochondria via autophagy (mitophagy). Here, we describe the involvement of parkin and PINK1 in a vesicular pathway regulating mitochondrial quality control. This pathway is distinct from canonical mitophagy and is triggered by the generation of oxidative stress from within mitochondria. Wild-type but not PD-linked mutant parkin supports the biogenesis of a population of mitochondria-derived vesicles (MDVs), which bud off mitochondria and contain a specific repertoire of cargo proteins. These MDVs require PINK1 expression and ultimately target to lysosomes for degradation. We hypothesize that loss of this parkin- and PINK1-dependent trafficking mechanism impairs the ability of mitochondria to selectively degrade oxidized and damaged proteins leading, over time, to the mitochondrial dysfunction noted in PD.
              Article 0 comments Cited 282 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-ta): Life Sci Alliance
                Journal ID (iso-abbrev): Life Sci Alliance
                Journal ID (hwp): lsa
                Journal ID (publisher-id): lsa
                Title: Life Science Alliance
                Publisher: Life Science Alliance LLC
                ISSN (Electronic): 2575-1077
                Publication date (Electronic): 15 April 2019
                Publication date Collection: April 2019
                Publication date PMC-release: 15 April 2019
                Volume: 2
                Issue: 2
                Electronic Location Identifier: e201900392
                Affiliations
                [1 ]Fondazione Ospedale San Camillo, IRCCS, Venezia, Italy
                [2 ]MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, UK
                [3 ]Department of Biology, University of Padova, Padova, Italy
                [4 ]Neurogenetics and Behavior of Drosophila Lab, Department of Biology, University of Padova, Padova, Italy
                [5 ]Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy
                Author notes
                Author information
                https://orcid.org/0000-0002-2728-6251
                https://orcid.org/0000-0002-3530-2565
                https://orcid.org/0000-0002-2489-9116
                https://orcid.org/0000-0002-1154-6629
                https://orcid.org/0000-0002-0864-8309
                Article
                Publisher ID: LSA-2019-00392
                DOI: 10.26508/lsa.201900392
                PMC ID: 6467245
                PubMed ID: 30988163
                SO-VID: 64ec8cdc-40f7-46b4-89d8-e43d64c26caf
                Copyright © © 2019 von Stockum et al.
                License:

                This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 1 April 2019
                Date revision received : 4 April 2019
                Date accepted : 5 April 2019
                Funding
                Funded by: Italian Ministry of Health “Ricerca Finalizzata”;
                Award ID: GR-2011-02351151
                Funded by: Rita Levi Montalcini “Brain Gain”;
                Funded by: Michael J Fox RRIA 2014;
                Award ID: 9795
                Award Recipient :
                Funded by: ERC;
                Award ID: FP7-282280
                Award ID: FP7 CIG PCIG13-GA-2013-618697
                Funded by: Italian Ministry of Research FIRB RBAP11Z3YA_005;
                Award Recipient :
                Funded by: MRC Core;
                Award ID: MC_UU_00015/6
                Award Recipient :
                Funded by: Wellcome Trust;
                Award ID: 084757
                Categories
                Subject: Research Article
                Subject: Research Articles
                Subject: 4
                Subject: 19

                Data availability:

                Comments

                Comment on this article

                scite_

                Similar content28

                See all similar

                Cited by13

                See all cited by

                Most referenced authors1,176

                See all reference authors