Pathogenic SOD1 Proteins and Oxidative Chemistry

SOD1 has an elegantly designed active site channel that provides electrostatic guidance of the negatively charged substrate to the catalytic copper ion while simultaneously preventing larger anionic molecules from entering. It has been hypothesized that mutations within SOD1 could cause a 'loosening' of its structure, thereby compromising the selectivity provided by the active site channel [29]. It has also been suggested that the deleterious gain-of-function property comes from an altered reactivity of the catalytic copper resulting in the production of damaging oxidants [30,31]. Possible aberrant oxidative activities of pathogenic SOD1 proteins include enhanced peroxidase activity, elevated peroxynitrate production, or other oxidative reactions that may arise from any mishandled copper ion that may become released from the protein.

Several pathogenic mutants of SOD1 have been demonstrated to have a significantly enhanced peroxidase activity relative to the wild-type enzyme [23,32-36]. The normal SOD1 disproportionation reaction produces hydrogen peroxide from superoxide anion, but when hydrogen peroxide levels rise, it can also act as a substrate, resulting in the production of a powerful oxidant (hydroxyl radical) as shown in Reactions (3) and (4).

SOD1-Cu2+ + H2O2 ^ SOD1-Cu1+ + O-SOD1-Cu1+ + H2O2 ^ SOD1-Cu2+(OH') + OH

This chemistry is known to be dramatically enhanced in the presence of bicarbonate anion, the concentrations of which are substantial (~25mM) in vivo [36]. The presence of bicarbonate also permits the oxidation of exogenous substrates too large to enter the active site channel, although there is debate as to the exact molecular/chemical basis for this property [36-41]. In this context, it is possible that certain proteins (such as signaling molecules) or other factors critical for motor neuron viability become oxidized in the presence of pathogenic SOD1 proteins, which could eventually lead to motor neuron dysfunction.

An alternative oxidative pathway involves the production of peroxynitrite (ONOO-). Peroxynitrite is produced spontaneously from the reaction of nitric oxide and superoxide (Reaction 5).

It has been postulated that when peroxynitrite levels rise, pathogenic SOD1 proteins could catalyze the nitration of tyrosine residues as shown in Reactions (6) and (7) [22,42-44].

SOD1-CuO-NO+ + H-Tyr ^ SOD1-Cu2+ + OH- + NO2-Tyr (7)

In support of this idea, increased protein nitration in various fALS SOD1 backgrounds has been documented [42,44,45]. However, studies in transgenic mice engineered such that they have substantially decreased nitric oxide production did not affect the disease onset or progression [46].

A prerequisite for fALS SOD1 proteins to engage in oxidative reactions is that these proteins must bind copper (or another redox active metal ion) in the active site. However, many fALS-associated SOD1 mutants are known to be metal-deficient, particularly with respect to copper ion [47,48]. Moreover, a study of transgenic mice that lack the copper chaperone for superoxide dismutase (CCS) and therefore express copper-deficient pathogenic SOD1 proteins did not demonstrate slowed progression of motor neuron disease [49]. Similarly, SOD1 mutants with an abrogated copper binding site were still able to cause the disease when expressed in transgenic animals [50,51].

The observations described above seem to suggest that fALS SOD1-catalyzed oxidative chemistry may not be directly involved in disease etiology. However, oxidative stress from other sources may in general be involved in ALS pathogen-esis [52] and in particular, self-oxidation may play a role in pathogenic SOD1

aggregation (see Section 2.3). Of interest is the late onset of the disorder, a characteristic common to other neurodegenerative diseases. It is well established that oxidative damage increases with age [53] and that copper and iron levels increase in concentration in the brain [54,55]. In addition, there exists evidence of oxidative stress in certain tissues of ALS patients [56-58]. One possibility is that the observed oxidative damage could represent a downstream effect of motor neuron dysfunction, particularly since mitochondrial abnormalities are among the earliest signs of pathology in the ALS transgenic mice [27]. In vitro studies have shown that mild oxidative damage to SOD1 results in an increased propensity for the molecule to be subjected to proteasomal digestion [59] and/or aggregation [60].

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