Cytotoxicity of superoxide dismutase 1 in cultured cells is linked to Zn2+ chelation.

PloS One
Ann-Sofi JohanssonMikael Oliveberg

Abstract

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 Zn(2+) ions from the growth medium. The decreased cell viability that accompanies this extraction is presumably based on disturbed Zn(2+) homeostasis. Consistently, mutations that cause global unfolding of the apoSOD1 molecule or otherwise reduce its Zn(2+) affinity abolish completely the cytotoxic response. So does the addition of surplus Zn(2+). Taken together, these observat...Continue Reading

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Citations

Apr 17, 2014·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Axel AbeleinSebastian K T S Wärmländer
Mar 26, 2016·Frontiers in Pediatrics·Gyuyoup KimEung-Kwon Pae
Sep 23, 2018·Scientific Reports·Bastien ParéFrançois Gros-Louis
Jul 28, 2019·Biochimica Et Biophysica Acta. General Subjects·A TakahashiT Nakabayashi
Dec 22, 2019·Free Radical Biology & Medicine·Itsuki AnzaiYoshiaki Furukawa

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Methods Mentioned

BETA
size-exclusion chromatography
NMR
gel
ion-exchange chromatography
X-ray
Fluorescence
Fluorescence microscopy

Software Mentioned

nmrPipe
Sparky
Graphpad prism
MultiGauge
Quantity One

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