{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T12:19:19Z","timestamp":1764332359203},"reference-count":68,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,3,2]],"date-time":"2016-03-02T00:00:00Z","timestamp":1456876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["606609"],"award-info":[{"award-number":["606609"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label \/><jats:p>Glutathione (<jats:styled-content style=\"fixed-case\">GSH<\/jats:styled-content>) is a tripeptide often considered to be the master antioxidant in cells. <jats:styled-content style=\"fixed-case\">GSH<\/jats:styled-content> plays an integral role in cellular redox regulation and is also known to have a role in mammalian copper homeostasis. <jats:italic>In vitro<\/jats:italic> evidence suggests that <jats:styled-content style=\"fixed-case\">GSH<\/jats:styled-content> is involved in copper uptake, sequestration and efflux. This study was undertaken to further investigate the roles that <jats:styled-content style=\"fixed-case\">GSH<\/jats:styled-content> plays in neuronal copper homeostasis <jats:italic>in\u00a0vivo<\/jats:italic>, using the model organism <jats:italic>Drosophila melanogaster<\/jats:italic>. <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> interference\u2010mediated knockdown of the Glutamate\u2010cysteine ligase catalytic subunit gene (<jats:italic>Gclc<\/jats:italic>) that encodes the rate\u2010limiting enzyme in <jats:styled-content style=\"fixed-case\">GSH<\/jats:styled-content> biosynthesis was utilised to genetically deplete <jats:styled-content style=\"fixed-case\">GSH<\/jats:styled-content> levels. When <jats:italic>Gclc<\/jats:italic> was knocked down in all neurons, this caused lethality, which was partially rescued by copper supplementation and was exacerbated by additional knockdown of the copper uptake transporter <jats:italic>Ctr1A<\/jats:italic>, or over\u2010expression of the copper efflux transporter <jats:italic><jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>7<\/jats:italic>. Furthermore, when <jats:italic>Gclc<\/jats:italic> was knocked down in a subset of neuropeptide\u2010producing cells, this resulted in adult progeny with unexpanded wings, a phenotype previously associated with copper dyshomeostasis. In these cells, <jats:italic>Gclc<\/jats:italic> suppression caused a decrease in axon branching, a phenotype further enhanced by <jats:italic><jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>7<\/jats:italic> over\u2010expression. Therefore, we conclude that <jats:styled-content style=\"fixed-case\">GSH<\/jats:styled-content> may play an important role in regulating neuronal copper levels and that reduction in <jats:styled-content style=\"fixed-case\">GSH<\/jats:styled-content> may lead to functional copper deficiency in neurons <jats:italic>in\u00a0vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:label \/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13567-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>We provide genetic evidence that glutathione (GSH) levels influence Cu content or distribution <jats:italic>in\u00a0vivo<\/jats:italic>, in <jats:italic>Drosophila<\/jats:italic> neurons. GSH could be required for binding Cu imported by Ctr1A and distributing it to chaperones, such as Mtn, CCS and Atox1. Alternatively, GSH could modify the copper\u2010binding and transport activities of Atox1 and the ATP7 efflux protein via glutathionylation of copper\u2010binding cysteines.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13567","type":"journal-article","created":{"date-parts":[[2016,2,7]],"date-time":"2016-02-07T01:57:01Z","timestamp":1454810221000},"page":"360-370","source":"Crossref","is-referenced-by-count":26,"title":["Reduced glutathione biosynthesis in <i>Drosophila melanogaster<\/i> causes neuronal defects linked to copper deficiency"],"prefix":"10.1111","volume":"137","author":[{"given":"Stephen W.","family":"Mercer","sequence":"first","affiliation":[{"name":"School of Biological Sciences Monash University Melbourne Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharon","family":"La Fontaine","sequence":"additional","affiliation":[{"name":"School of Life and Environmental Sciences Centre for Molecular and Medical Research and Centre for Cellular and Molecular Biology Deakin University Burwood Victoria Australia"},{"name":"The Florey Institute of Neuroscience and Mental Health Parkville Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Coral G.","family":"Warr","sequence":"additional","affiliation":[{"name":"School of Biological Sciences Monash University Melbourne Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Burke","sequence":"additional","affiliation":[{"name":"School of Biological Sciences Monash University Melbourne Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,3,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60196-2"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09018"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(98)00055-0"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00775-010-0629-y"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4MT00020J"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.1999.tb00216.x"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308298101"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0193-14"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2015.07.006"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.009902"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M507065200"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-02-00562.1999"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2006.11.018"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj2920673"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj2920673"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(89)91693-8"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)83589-X"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/10715769900300841"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.381178"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4511"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4MT00140K"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.5.1913"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-7091-6360-3_1"},{"issue":"1","key":"e_1_2_7_25_1","first-page":"24","article-title":"Oxidative mechanisms in nigral cell death in Parkinson's disease","volume":"13","author":"Jenner P.","year":"1998","journal-title":"Mov. 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