AUTHOR=Furukawa Yoshiaki 

TITLE=Redox environment is an intracellular factor to operate distinct pathways for aggregation of Cu,Zn-superoxide dismutase in amyotrophic lateral sclerosis

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=7

YEAR=2013

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2013.00240

DOI=10.3389/fncel.2013.00240

ISSN=1662-5102

ABSTRACT=<p>Dominant mutations in Cu,Zn-superoxide dismutase (SOD1) cause a familial form of amyotrophic lateral sclerosis (fALS). Misfolding and aggregation of mutant SOD1 proteins are a pathological hallmark of SOD1-related fALS cases; however, the molecular mechanism of SOD1 aggregation remains controversial. Here, I have used <italic>E. coli</italic> as a model organism and shown multiple distinct pathways of SOD1 aggregation that are dependent upon its thiol-disulfide status. Overexpression of fALS-mutant SOD1s in the cytoplasm of <italic>E. coli</italic> BL21 and SHuffle<sup>TM</sup>, where redox environment is reducing and oxidizing, respectively, resulted in the formation of insoluble aggregates with notable differences; a disulfide bond of SOD1 was completely reduced in BL21 or abnormally formed between SOD1 molecules in SHuffle<sup>TM</sup>. Depending upon intracellular redox environment, therefore, mutant SOD1 is considered to misfold/aggregate through distinct pathways, which would be relevant in description of the pathological heterogeneity of SOD1-related fALS cases.</p>