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Huntingtin inclusion bodies are iron-dependent centers of oxidative events

Huntingtin inclusion bodies are iron-dependent centers of oxidative events
Huntingtin inclusion bodies are iron-dependent centers of oxidative events
Recently, we reported that the transient expression of huntingtin exon1 polypeptide containing polyglutamine tracts of various sizes (httEx1-polyQ) in cell models of Huntington disease generated an oxidative stress whose intensity was CAG repeat expansion-dependent. Here, we have analyzed the intracellular localization of the oxidative events generated by the httEx1-polyQ polypeptides. Analysis of live COS-7 cells as well as neuronal SK-N-SH and PC12 cells incubated with hydroethidine or dichlorofluorescein diacetate revealed oxidation of these probes at the level of the inclusion bodies formed by httEx1-polyQ polypeptides. The intensity and frequency of the oxidative events among the inclusions were CAG repeat expansion-dependent. Electron microscopic analysis of cell sections revealed the presence of oxidation-dependent morphologic alterations in the vicinity of httEx1-polyQ inclusion bodies. Moreover, a high level of oxidized proteins was recovered in partially purified inclusions. We also report that the iron chelator deferroxamine altered the structure, localization and oxidative potential of httEx1-polyQ inclusion bodies. Hence, despite the fact that the formation of inclusion bodies may represent a defense reaction of the cell to eliminate httEx1 mutant polypeptide, this phenomenon appears inherent to the generation of iron-dependent oxidative events that can be deleterious to the cell.
HSPS, huntingtin, inclusion bodies, iron, ROS
1742-464X
5428-5441
Firdaus, Wance J.J.
5d748a14-2027-4e6f-bdff-c4150a01745a
Wyttenbach, Andreas
05019897-52b1-4bb6-b259-5d51abae7540
Giuliano, Paola
8725e331-d71e-48d9-80f5-e5d4dbd1c336
Kretz-Remy, Carole
11e866f4-1d19-4c06-8e53-5b23794ec0c9
Currie, R. William
7178e4b6-974b-46a9-aacf-d22e8640c6de
Arrigo, André-Patrick
7decf171-e4f8-4142-a52f-ae9251092e95
Firdaus, Wance J.J.
5d748a14-2027-4e6f-bdff-c4150a01745a
Wyttenbach, Andreas
05019897-52b1-4bb6-b259-5d51abae7540
Giuliano, Paola
8725e331-d71e-48d9-80f5-e5d4dbd1c336
Kretz-Remy, Carole
11e866f4-1d19-4c06-8e53-5b23794ec0c9
Currie, R. William
7178e4b6-974b-46a9-aacf-d22e8640c6de
Arrigo, André-Patrick
7decf171-e4f8-4142-a52f-ae9251092e95

Firdaus, Wance J.J., Wyttenbach, Andreas, Giuliano, Paola, Kretz-Remy, Carole, Currie, R. William and Arrigo, André-Patrick (2006) Huntingtin inclusion bodies are iron-dependent centers of oxidative events. Febs Journal, 273 (23), 5428-5441. (doi:10.1111/j.1742-4658.2006.05537.x).

Record type: Article

Abstract

Recently, we reported that the transient expression of huntingtin exon1 polypeptide containing polyglutamine tracts of various sizes (httEx1-polyQ) in cell models of Huntington disease generated an oxidative stress whose intensity was CAG repeat expansion-dependent. Here, we have analyzed the intracellular localization of the oxidative events generated by the httEx1-polyQ polypeptides. Analysis of live COS-7 cells as well as neuronal SK-N-SH and PC12 cells incubated with hydroethidine or dichlorofluorescein diacetate revealed oxidation of these probes at the level of the inclusion bodies formed by httEx1-polyQ polypeptides. The intensity and frequency of the oxidative events among the inclusions were CAG repeat expansion-dependent. Electron microscopic analysis of cell sections revealed the presence of oxidation-dependent morphologic alterations in the vicinity of httEx1-polyQ inclusion bodies. Moreover, a high level of oxidized proteins was recovered in partially purified inclusions. We also report that the iron chelator deferroxamine altered the structure, localization and oxidative potential of httEx1-polyQ inclusion bodies. Hence, despite the fact that the formation of inclusion bodies may represent a defense reaction of the cell to eliminate httEx1 mutant polypeptide, this phenomenon appears inherent to the generation of iron-dependent oxidative events that can be deleterious to the cell.

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More information

Published date: 1 December 2006
Keywords: HSPS, huntingtin, inclusion bodies, iron, ROS

Identifiers

Local EPrints ID: 56800
URI: http://eprints.soton.ac.uk/id/eprint/56800
ISSN: 1742-464X
PURE UUID: 969b584d-b265-4d0a-9f90-e398aace91a0

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Date deposited: 06 Aug 2008
Last modified: 15 Mar 2024 11:03

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Contributors

Author: Wance J.J. Firdaus
Author: Andreas Wyttenbach
Author: Paola Giuliano
Author: Carole Kretz-Remy
Author: R. William Currie
Author: André-Patrick Arrigo

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