Human Molecular Genetics Advance Access published online on March 12, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn063
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Biological effects of CCS in the absence of SOD1 enzyme activation: implications for disease in a mouse model for ALS
1 Division of Toxicological Sciences, Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health Baltimore, MD 21205 2 Department of Neurology; University of Texas, Southwestern Medical Center, Dallas, TX, 75390
* To whom correspondence should be addressed vculotta{at}jhsph.edu 615 N. Wolfe St room E7626 Baltimore, MD 21205 Phone 410-955-3029 Fax 410-955-0116
Received November 14, 2007; Revised February 27, 2008; Accepted February 27, 2008
The CCS copper chaperone is critical for maturation of Cu, Zn-superoxide dismutase (SOD1) through insertion of the copper co-factor and oxidization of an intra-subunit disulfide. The disulfide helps stabilize the SOD1 polypeptide, which can be particularly important in cases of amyotrophic lateral sclerosis (ALS) linked to misfolding of mutant SOD1. Surprisingly however, over-expressed CCS was recently shown to greatly accelerate disease in a G93A SOD1 mouse model for ALS. Herein we show that disease in these G93A/CCS mice correlates with incomplete oxidation of the SOD1 disulfide. In the brain and spinal cord, CCS over-expression failed to enhance oxidation of the G93A SOD1 disulfide and if anything, effected some accumulation of disulfide-reduced SOD1. This effect was mirrored in culture with a C244, 246S mutant of CCS that has the capacity to interact with SOD1 but can neither insert copper nor oxidize the disulfide. In spite of disulfide effects, there was no evidence for increased SOD1 aggregation. If anything, CCS over-expression prevented SOD1 misfolding in culture as monitored by detergent insolubility. This protection against SOD1 misfolding does not require SOD1 enzyme activation as the same effect was obtained with the C244, 246S allele of CCS. In the G93A SOD1 mouse, CCS over-expression was likewise associated with a lack of obvious SOD1 misfolding marked by detergent-insolubility. CCS over-expression accelerates SOD1-linked disease without the hallmarks of misfolding and aggregation seen in other mutant SOD1 models. These studies are the first to indicate biological effects of CCS in the absence of SOD1 enzymatic activation.
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