Heterodimer formation of wild-type and amyotrophic lateral sclerosis-causing mutant Cu/Zn-Superoxide dismutase induces toxicity independent of protein aggregation
Heidrun Witan1, Andreas Kern1, Ingrid Koziollek-Drechsler1, Rebecca Wade2, Christian Behl1,* and Albrecht M. Clement1,*
1 Department of Pathobiochemistry, Johannes Gutenberg-University of Mainz, Medical School, Duesbergweg 6, 55099 Mainz 2 EML Research, Schloss-Wolfsbrunnenweg 33, 69118 Heidelberg

* Correspondence: Albrecht M. Clement (clement@uni-mainz.de) and Christian Behl (cbehl@uni-mainz.de), Duesbergweg 6, 55099 Mainz, Fax: xx49-6131-3925792

Received January 17, 2008; Revised January 20, 2008; Accepted January 20, 2008

Recent studies provide evidence that wild type Cu/Zn-superoxide dismutase (hWTSOD1) might be an important factor in mutant SOD1-mediated ALS. In order to investigate its functional role in the pathogenesis of ALS, we designed fusion proteins of two SOD1 monomers linked by a polypeptide. We demonstrated that wild-type like mutants, but not G85RSOD1 homodimers, as well as mutant heterodimers including G85RSOD1-hWTSOD1 display dismutase activity. Mutant homodimers showed an increased aggregation compared to the corresponding heterodimers in cell cultures and transgenic C. elegans, although G85RSOD1 heterodimers are more toxic in functional assays. Our data show that (i) toxicity of mutant SOD1 is not correlated to its aggregation potential; (ii) dismutase inactive mutants form dismutase active heterodimers with hWTSOD1; (iii) hWTSOD1 can be converted to contribute to disease by forming active heterodimers. Therefore we conclude that toxicity of mutant SOD1 is at least partially mediated through heterodimer formation with hWTSOD1 in vivo and does not correlate with the aggregation potential of individual mutants.

http://hmg.oxfordjournals.org/cgi/co...short/ddn025v1