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Cytotoxicity of Superoxide Dismutase 1 in Cultured Cells Is Linked to Zn2+ Chelation
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
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2012 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 7, no 4, e36104- p.Article in journal (Refereed) Published
Abstract [en]

Neurodegeneration in protein-misfolding disease is generally assigned to toxic function of small, soluble protein aggregates. Largely, these assignments are based on observations of cultured neural cells where the suspect protein material is titrated directly into the growth medium. In the present study, we use this approach to shed light on the cytotoxic action of the metalloenzyme Cu/Zn superoxide dismutase 1 (SOD1), associated with misfolding and aggregation in amyotrophic lateral sclerosis (ALS). The results show, somewhat unexpectedly, that the toxic species of SOD1 in this type of experimental setting is not an aggregate, as typically observed for proteins implicated in other neuro-degenerative diseases, but the folded and fully soluble apo protein. Moreover, we demonstrate that the toxic action of apoSOD1 relies on the protein's ability to chelate Zn2+ ions from the growth medium. The decreased cell viability that accompanies this extraction is presumably based on disturbed Zn2+ homeostasis. Consistently, mutations that cause global unfolding of the apoSOD1 molecule or otherwise reduce its Zn2+ affinity abolish completely the cytotoxic response. So does the addition of surplus Zn2+. Taken together, these observations point at a case where the toxic response of cultured cells might not be related to human pathology but stems from the intrinsic limitations of a simplified cell model. There are several ways proteins can kill cultured neural cells but all of these need not to be relevant for neurodegenerative disease.

Place, publisher, year, edition, pages
2012. Vol. 7, no 4, e36104- p.
National Category
Microbiology in the medical area Neurosciences
URN: urn:nbn:se:umu:diva-57388DOI: 10.1371/journal.pone.0036104ISI: 000305345200116OAI: diva2:541366
Available from: 2012-07-17 Created: 2012-07-16 Last updated: 2012-07-17Bibliographically approved

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Vestling, MonikaZetterström, PerMarklund, Stefan L.
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