Reduced glutathione biosynthesis in Drosophila melanogaster causes neuronal defects linked to copper deficiency.

Mercer, Stephen W, La Fontaine, Sharon, Warr, Carol G and Burke, Richard 2016, Reduced glutathione biosynthesis in Drosophila melanogaster causes neuronal defects linked to copper deficiency., Journal of neurochemistry, vol. 137, no. 3, pp. 360-370, doi: 10.1111/jnc.13567.

Attached Files
Name Description MIMEType Size Downloads

Title Reduced glutathione biosynthesis in Drosophila melanogaster causes neuronal defects linked to copper deficiency.
Author(s) Mercer, Stephen W
La Fontaine, SharonORCID iD for La Fontaine, Sharon orcid.org/0000-0002-9948-074X
Warr, Carol G
Burke, Richard
Journal name Journal of neurochemistry
Volume number 137
Issue number 3
Start page 360
End page 370
Total pages 11
Publisher Wiley
Place of publication Chichester, Eng.
Publication date 2016-05
ISSN 1471-4159
Keyword(s) ATP7
CTR1
Drosophila
copper
glutamate-cysteine ligase
glutathione
Summary Glutathione (GSH) is a tripeptide often considered to be the master antioxidant in cells. GSH plays an integral role in cellular redox regulation and is also known to have a role in mammalian copper homeostasis. In vitro evidence suggests that GSH is involved in copper uptake, sequestration and efflux. This study was undertaken to further investigate the roles that GSH plays in neuronal copper homeostasis in vivo, using the model organism Drosophila melanogaster. RNA interference-mediated knockdown of the Glutamate-cysteine ligase catalytic subunit gene (Gclc) that encodes the rate-limiting enzyme in GSH biosynthesis was utilised to genetically deplete GSH levels. When Gclc 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 Ctr1A, or over-expression of the copper efflux transporter ATP7. Furthermore, when Gclc was knocked down in a subset of neuropeptide-producing cells, this resulted in adult progeny with unexpanded wings, a phenotype previously associated with copper dyshomeostasis. In these cells, Gclc suppression caused a decrease in axon branching, a phenotype further enhanced by ATP7 over-expression. Therefore, we conclude that GSH may play an important role in regulating neuronal copper levels and that reduction in GSH may lead to functional copper deficiency in neurons in vivo. We provide genetic evidence that glutathione (GSH) levels influence Cu content or distribution in vivo, in Drosophila 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-binding and transport activities of Atox1 and the ATP7 efflux protein via glutathionylation of copper-binding cysteines.
Language eng
DOI 10.1111/jnc.13567
Field of Research 110999 Neurosciences not elsewhere classified
119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, Wiley
Persistent URL http://hdl.handle.net/10536/DRO/DU:30084959

Connect to link resolver
 
Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved.

Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 6 times in TR Web of Science
Scopus Citation Count Cited 8 times in Scopus
Google Scholar Search Google Scholar
Access Statistics: 186 Abstract Views, 6 File Downloads  -  Detailed Statistics
Created: Sun, 17 Jul 2016, 12:16:23 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.