Folding and Aggregation of Cu, Zn-Superoxide Dismutase

Abstract

1.1 ALS and SOD1 In 1993, a genetic link was established between amyotrophic lateral sclerosis (ALS) and mutant forms of Cu,Zn superoxide dismutase (SOD1) (Deng et al. 1993; Rosen et al. 1993), an antioxidant enzyme that catalyzes the dismutation of the damaging free radical superoxide anion (O2-) to hydrogen peroxide (H2O2) and diatomic oxygen (O2) via cyclic reduction and oxidation of a protein-bound Cu ion (Valentine et al. 2005). Today, over 150, predominantly missense mutations have been identified at ~75 sites spread throughout the protein (http://alsod.iop.kcl.ac.uk/). SOD1 mutations are found in ~1520% of inherited or familial ALS (fALS) cases and in a small percentage of sporadic ALS (sALS) cases (Rosen et al. 1993; Kato et al. 2000; Liu et al. 2009; Forsberg et al. 2011). fALS accounts for ~10% of all ALS cases and so SOD1 mutations comprise ~1.5-2% of all ALS cases, but nevertheless represent a major known cause of the disease. The clinical symptoms of fALS and sALS are similar, yet fALS patients with SOD1 mutations have an earlier age of disease onset than sALS (by ~10 years) (Wijesekera and Leigh 2009). Furthermore, while the age of disease onset has not been identified as statistically different between different SOD1 mutations, disease duration for each mutation is often different, ranging from shorter (e.g. ~1 year for A4V, the most common mutation in North America) than the typical 3-5 years to longer (e.g. ~18 years for H46R) (Cudkowicz et al. 1997; Valentine et al. 2005; Wang et al. 2008). In humans and murine models of ALS, mutations in the gene encoding SOD1 are typically autosomal dominant and are associated with a toxic gain of function. Despite extensive research, the molecular basis for mutant SOD1 toxicity remains unclear (Valentine et al. 2005; Boillee et al. 2006; Ilieva et al. 2009). Extensive research has been conducted on SOD1-linked fALS, as understanding and treatment of this disease may be relevant to ALS in general. While ALS patients share many clinical symptoms, numerous genes have been linked to ALS, and there is evidence for differences in pathology related to both genetic and environmental factors; hence, ALS is a syndrome and not a single disease with unique pathology (Cozzolino et al. 2008).