**1. Introduction**

248 Amyotrophic Lateral Sclerosis

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Mutations in Cu/Zn superoxide dismutase (SOD1) gene are linked to the motor neuron death in familial amyotrophic lateral sclerosis (FALS). More than 100 missense mutations have been described to cause the disease and are distributed throughout the whole 153 amino acid sequence of SOD1 molecule (Valentine et al., 2005; Boillée et al., 2006). Mutant SOD1 molecules can be grouped according to their biochemical characteristics into wild type-like proteins, that bind metal ions and possess enzymatic dismutase activity (e.g. G93A-SOD1 and G37R-SOD1), and mutant molecules with impaired metal binding capacity, which have significantly reduced dismutase activity (e.g. G85R-SOD1) (Valentine et al., 2005). Therefore, the toxicity of mutant SOD1 is not thought to be mediated by a lack of dismutase activity, but rather by gain of one or more detrimental functions.

The exact nature of the toxic gain of function for mutant SOD1 has not been identified yet. Most of the studies demonstrate a link between the disease pathology and increased oxidative stress. Augmented generation of free radicals and reactive oxygen species (ROS) is thought to be a major contributor to the destruction of motor neurons (Beckman et al., 1994; Wiedau-Pazos et al., 1996; Estévez et al., 1999).

The suggested toxic mechanisms include aberrant mutant SOD1 enzymatic activities (Beckman et al., 1993; Wiedau-Pazos et al., 1996) as well as destabilized SOD1 protein misfolding, causing enhanced aggregation of SOD1 or pathological interaction of SOD1 with other proteins (Stathopulos et al., 2003; Liu et al., 2004).

In a number of studies mitochondrial localization of mutant SOD1 has been implicated in ALS pathogenesis (Liu et al., 2004; Vijayvergiya et al., 2005; Bergemalm et al., 2006; Deng et al., 2006; Ferri et al., 2006) and increased recruitment of mutant SOD1 into mitochondria in the spinal cord might be a reason for death of motor neurons in some forms of familial ALS. However, the detailed mechanisms for toxicity of the mitochondria resident mutant SOD1 are not entirely clear yet. Here we review the current state of the art in the studies on mitochondrial toxicity of SOD1 in ALS.
