Abstract
Protein misfolding is implicated in neurodegenerative diseases such as ALS, where mutations of superoxide dismutase 1 (SOD1) account for about 20% of the inherited mutations. Human SOD1 (hSOD1) contains four cysteines, including Cys(57) and Cys(146), which have been linked to protein stability and folding via forming a disulfide bond, and Cys(6) and Cys(111) as free thiols. But the roles of the cellular oxidation-reduction (redox) environment in SOD1 folding and aggregation are not well understood. Here we explore the effects of cellular redox systems on the aggregation of hSOD1 proteins. We found that the known hSOD1 mutations G93A and A4V increased the capability of the thioredoxin and glutaredoxin systems to reduce hSOD1 compared with wild-type hSOD1. Treatment with inhibitors of these redox systems resulted in an increase of hSOD1 aggregates in the cytoplasm of cells transfected with mutants but not in cells transfected with wild-type hSOD1 or those containing a secondary C111G mutation. This aggregation may be coupled to changes in the redox state of the G93A and A4V mutants upon mild oxidative stress. These results strongly suggest that the thioredoxin and glutaredoxin systems are the key regulators for hSOD1 aggregation and may play critical roles in the pathogenesis of ALS.
Highlights
ALS is a neurodegenerative disease in which the main feature is a loss of motoneurons and muscle atrophy
We found that the known Human SOD1 (hSOD1) mutations G93A and A4V increased the capability of the thioredoxin and glutaredoxin systems to reduce hSOD1 compared with wild-type hSOD1
Reduction of hSOD1 by the Thioredoxin and GSH-Grx Systems in Vitro—To detect whether the mutations in ALS-linked superoxide dismutase 1 (SOD1) affect the susceptibility of SOD1 to reductants, we investigated the reduction of the WT and mutants G93A and A4V of hSOD1 by the GSH-Grx and Trx systems (Fig. 2A)
Summary
ALS is a neurodegenerative disease in which the main feature is a loss of motoneurons and muscle atrophy. Changes in the cytoplasmic redox potential would influence the reduction or the oxidation of the disulfide bond of WT or mutant SOD1 proteins, rendering reactive free cysteines that could interact with thiol groups of other molecules forming new aggregates.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
