For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
13
views
53
references
 Top references
cited by
11
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      239
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Metal Homeostasis Regulators Suppress FRDA Phenotypes in a Drosophila Model of the Disease

      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

          Friedreich’s ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. By means of a candidate genetic screen, we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin deficiency-induced phenotypes. Taken together, these results demonstrate that the metal dysregulation in FRDA includes other metals besides iron, therefore providing a new set of potential therapeutic targets.

          Related collections

          Most cited references53

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

          Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits.

          Hélène Puccio, Delphine Simon, Mireille Cossée … (2001)
          Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy and increased incidence in diabetes. FRDA is caused by severely reduced levels of frataxin, a mitochondrial protein of unknown function. Yeast knockout models as well as histological and biochemical data from heart biopsies or autopsies of FRDA patients have shown that frataxin defects cause a specific iron-sulfur protein deficiency and intramitochondrial iron accumulation. We have recently shown that complete absence of frataxin in the mouse leads to early embryonic lethality, demonstrating an important role for frataxin during mouse development. Through a conditional gene-targeting approach, we have generated in parallel a striated muscle frataxin-deficient line and a neuron/cardiac muscle frataxin-deficient line, which together reproduce important progressive pathophysiological and biochemical features of the human disease: cardiac hypertrophy without skeletal muscle involvement, large sensory neuron dysfunction without alteration of the small sensory and motor neurons, and deficient activities of complexes I-III of the respiratory chain and of the aconitases. Our models demonstrate time-dependent intramitochondrial iron accumulation in a frataxin-deficient mammal, which occurs after onset of the pathology and after inactivation of the Fe-S-dependent enzymes. These mutant mice represent the first mammalian models to evaluate treatment strategies for the human disease.
          Article 0 comments Cited 164 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin.

            M Babcock, D. de Beer, Jamie Oaks … (1997)
            The gene responsible for Friedreich's ataxia, a disease characterized by neurodegeneration and cardiomyopathy, has recently been cloned and its product designated frataxin. A gene in Saccharomyces cerevisiae was characterized whose predicted protein product has high sequence similarity to the human frataxin protein. The yeast gene (yeast frataxin homolog, YFH1) encodes a mitochondrial protein involved in iron homeostasis and respiratory function. Human frataxin also was shown to be a mitochondrial protein. Characterizing the mechanism by which YFH1 regulates iron homeostasis in yeast may help to define the pathologic process leading to cell damage in Friedreich's ataxia.
            Article 0 comments Cited 139 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading.

              Stephanie Vendramini Bianco Duarte, Supak Jenkitkasemwong, Brian K Sparkman … (2012)
              ZIP8 (SLC39A8) belongs to the ZIP family of metal-ion transporters. Among the ZIP proteins, ZIP8 is most closely related to ZIP14, which can transport iron, zinc, manganese, and cadmium. Here we investigated the iron transport ability of ZIP8, its subcellular localization, pH dependence, and regulation by iron. Transfection of HEK 293T cells with ZIP8 cDNA enhanced the uptake of (59)Fe and (65)Zn by 200 and 40%, respectively, compared with controls. Excess iron inhibited the uptake of zinc and vice versa. In RNA-injected Xenopus oocytes, ZIP8-mediated (55)Fe(2+) transport was saturable (K(0.5) of ∼0.7 μm) and inhibited by zinc. ZIP8 also mediated the uptake of (109)Cd(2+), (57)Co(2+), (65)Zn(2+) > (54)Mn(2+), but not (64)Cu (I or II). By using immunofluorescence analysis, we found that ZIP8 expressed in HEK 293T cells localized to the plasma membrane and partially in early endosomes. Iron loading increased total and cell-surface levels of ZIP8 in H4IIE rat hepatoma cells. We also determined by using site-directed mutagenesis that asparagine residues 40, 88, and 96 of rat ZIP8 are glycosylated and that N-glycosylation is not required for iron or zinc transport. Analysis of 20 different human tissues revealed abundant ZIP8 expression in lung and placenta and showed that its expression profile differs markedly from ZIP14, suggesting nonredundant functions. Suppression of endogenous ZIP8 expression in BeWo cells, a placental cell line, reduced iron uptake by ∼40%, suggesting that ZIP8 participates in placental iron transport. Collectively, these data identify ZIP8 as an iron transport protein that may function in iron metabolism.
              Article 0 comments Cited 114 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Francesc Palau: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 19 July 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 7
                Electronic Location Identifier: e0159209
                Affiliations
                [1 ]Department of Genetics, University of Valencia, Burjassot, Valencia, Spain
                [2 ]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
                [3 ]Department of Biomaterials and Bioinspired Materials, Instituto de Ciencia de Materiales de Madrid/CSIC, Madrid, Spain
                [4 ]CIBERSAM, INCLIVA, Valencia, Spain
                Sant Joan de Déu Children's Hospital, SPAIN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MDM MJM-S JB SS JVL IA. Performed the experiments: SS PC-Q JVL LG. Analyzed the data: SS PC-Q JVL. Contributed reagents/materials/analysis tools: MDM JB MJM-S IA. Wrote the paper: SS MDM JVL JB MJM-S.

                [¤]

                Current address: Evolutionary Biology Center, Uppsala University, Uppsala, Sweden

                Article
                Publisher ID: PONE-D-16-03495
                DOI: 10.1371/journal.pone.0159209
                PMC ID: 4951068
                PubMed ID: 27433942
                SO-VID: ddc1487b-c2de-4603-812c-6320b7698116
                Copyright © © 2016 Soriano et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 25 January 2016
                Date accepted : 28 June 2016
                Page count
                Figures: 5, Tables: 0, Pages: 16
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004963, Seventh Framework Programme;
                Award ID: 242193 EFACTS
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100008666, Fundació la Marató de TV3;
                Award ID: 101932
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100003359, Generalitat Valenciana;
                Award ID: PROMETEOII/2014/067
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01-NS42179
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004837, Ministerio de Ciencia e Innovación;
                Award ID: AP2007-04050
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100003359, Generalitat Valenciana;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004963, Seventh Framework Programme;
                Award ID: 242193 EFACTS
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001961, AXA Research Fund;
                Award Recipient :
                This work was supported by grants from the European Community’s Seventh Framework Program FP7/2007-2013 [grant agreement no. 242193 EFACTS], the Fundació la Marató TV3 of Spain [exp 101932] and the Prometeo Program from Generalitat Valenciana [PROMETEOII/2014/067]. Work in the Botas laboratory was supported by the R01-NS42179 NIH grant. S.S. was a recipient of a fellowship from Ministerio de Ciencia e Innovación of Spain; P.C.-Q. is a recipient of a fellowship from Generalitat Valenciana of Spain, J.V.L. was supported by a research contract from the European Community’s Seventh Framework Program FP7/2007-2013 [grant agreement no. 242193 EFACTS] and L.G. is the beneficiary of a postdoctoral grant from the AXA Research Fund.
                Categories
                Subject: Research Article
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Elements
                Subject: Iron
                Subject: Research and Analysis Methods
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Drosophila Melanogaster
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Animals
                Subject: Invertebrates
                Subject: Arthropoda
                Subject: Insects
                Subject: Drosophila
                Subject: Drosophila Melanogaster
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Elements
                Subject: Zinc
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Eyes
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Eyes
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Eyes
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Eyes
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Phenotypes
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Homeostasis
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Homeostasis
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Gene Expression
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Oxidative Stress
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files.

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

                Comments

                Comment on this article

                scite_

                Similar content239

                See all similar

                Cited by11

                See all cited by

                Most referenced authors632

                See all reference authors