cytotoxicity of superoxide dismutase 1 in cultured cells is linked to zn2+ chelation在培养细胞超氧化物歧化酶1的细胞毒性与zn2 +螯合.pdfVIP

Cytotoxicity of Superoxide Dismutase 1 in Cultured Cells Is Linked to Zn2+ Chelation 1 2 ¨ 3 1 1 Ann-Sofi Johansson , Monika Vestling , Per Zetterstrom , Lisa Lang , Lina Leinartaite˙ , ¨ 1, Jens Danielsson 1, Stefan L. Marklund3, Mikael Oliveberg 1* Mikael Karlstrom ˚ ˚ 1 Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden, 2 Department of Medical Biochemistry and Biophysics, Umea University, Umea, ˚ ˚ Sweden, 3 Department of Medical Biosciences, Clinical chemistry, Umea University, Umea, Sweden 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