Change search
ReferencesLink to record
Permanent link

Direct link
Disulfide Scrambling in Superoxide Dismutase 1 Reduces Its Cytotoxic Effect in Cultured Cells and Promotes Protein Aggregation
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2013 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 10, e78060- p.Article in journal (Refereed) Published
Abstract [en]

Mutations in the gene coding for superoxide dismutase 1 (SOD1) are associated with familiar forms of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). These mutations are believed to result in a gain of toxic function, leading to neuronal degeneration. The exact mechanism is still unknown, but misfolding/aggregation events are generally acknowledged as important pathological events in this process. Recently, we observed that demetallated apoSOD1, with cysteine 6 and 111 substituted for alanine, is toxic to cultured neuroblastoma cells. This toxicity depended on an intact, high affinity Zn2+ site. It was therefor contradictory to discover that wild-type apoSOD1 was not toxic, despite of its high affinity for Zn2+. This inconsistency was hypothesized to originate from erroneous disulfide formation involving C6 and C111. Using high resolution non-reducing SDS-PAGE, we have in this study demonstrated that the inability of wild-type apoSOD1 to cause cell death stems from formation of non-native intramolecular disulfides. Moreover, monomeric apoSOD1 variants capable of such disulfide scrambling aggregated into ThT positive oligomers under physiological conditions without agitation. The oligomers were stabilized by intermolecular disulfides and morphologically resembled what has in other neurodegenerative diseases been termed protofibrils. Disulfide scrambling thus appears to be an important event for misfolding and aggregation of SOD1, but may also be significant for protein function involving cysteines, e. g. mitochondrial import and copper loading.

Place, publisher, year, edition, pages
2013. Vol. 8, no 10, e78060- p.
National Category
Biological Sciences
Research subject
URN: urn:nbn:se:su:diva-96646DOI: 10.1371/journal.pone.0078060ISI: 000325894100098OAI: diva2:667770


Available from: 2013-11-27 Created: 2013-11-25 Last updated: 2014-09-23Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Leinartaité, LinaJohansson, Ann-Sofi
By organisation
Department of Biochemistry and Biophysics
In the same journal
Biological Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 26 hits
ReferencesLink to record
Permanent link

Direct link