, 2009). More recently, mutant SOD1 models have been generated in zebrafish (Lemmens et al., 2007) and Caenorhabditis elegans (Witan et al., 2008; Wang et al., 2009a), suitable for genetic and small compound screening (Fig. 1). Almost all SOD1 mutations check details behave as autosomal dominant traits, and phenotype–genotype correlations have been described (Cudkowicz et al., 1998; Regal et al., 2006; Siddique & Siddique, 2008). One mutation, D90A, is recessive in populations of Scandinavian origin

but dominant in others (Andersen et al., 1995; Robberecht et al., 1996). The mechanism underlying the resistance of certain populations to monoallelic expression of this mutation (or the susceptibility of others) is of high interest but hitherto unknown. Not surprisingly, dysfunction of the axon, containing OSI-906 99% of the motor neuron cytoplasm,

is among the earliest manifestations of the mutant SOD1-induced degenerative process. This dysfunction appears as retraction of motor axons from neuromuscular junctions resulting in denervation and muscle weakness (Fischer et al., 2004). The pivotal significance of the axonal compartment explains the finding that preserving the cell body by interfering with the later stages of the degenerative process is insufficient to affect the clinical disease (Gould et al., 2006; Dewil et al., 2007a). A toxic gain-of-function of the mutant protein underlies motor neuron toxicity, as these rodent models retain their endogenous SOD1 activity and SOD1-deficient mice have no overt phenotype of motor neuron degeneration (Reaume et al., 1996).

The expression level of the SOD1 mutant protein for a given mutation determines disease severity, higher levels yielding a more aggressive phenotype. This has been well documented for the G93A-mutant SOD1 mouse model (Alexander et al., 2004; Fig. 2). The mechanism through which mutant SOD1 induces motor neuron degeneration remains Clomifene incompletely understood, even nearly two decades after their discovery, but most probably involves several (interacting) pathways rather than a single pathogenic mechanism. SOD1 is an important enzyme in the defence against superoxide anions, most of which are inadvertent reaction products in the mitochondria due to incomplete efficiency (‘leakiness’) of oxidative phosphorylation. Many studies have reported the presence of oxidative damage to proteins, lipids or DNA in patients with familial or sporadic ALS as well as in several mutant SOD1 mice (Barber & Shaw, 2010). It remains uncertain whether these changes are primary or secondary in nature. Two oxidation-modified proteins are particularly worth mentioning. SOD1 itself was found to be heavily oxidized (Andrus et al., 1998); this may at least contribute to the newly acquired toxic property of the protein (Ezzi et al., 2007).