SOD1 and ALS Sample Clauses

SOD1 and ALS. ‌ The first genetic defects associated with ALS were identified in the Cu/Zn superoxide dismutase (SOD1) gene in 1993 (Xxxxx et al., 1993). These account for approximately 20% of familial ALS and a small percentage of the sporadic cases (Millecamps et al., 2010) and until recently, SOD1 was believed to be the most common genetic cause for ALS . The identification of mutations in SOD1 facilitated the creation of the first transgenic ALS mouse models, which recapitulate the rapidly progressive motor neuron degeneration seen in human patients (Xxxxxx et al., 1994). SOD1 is a ubiquitously expressed antioxidant enzyme, which converts superoxide radicals to hydrogen peroxide and molecular oxygen. The protein is encoded by a single gene on chromosome 21 and to date, 166 different mutations have been reported involving most of its 153 amino acids (Xxxxxxxx and Xx-Xxxxxxx, 2011). It was first hypothesised that loss of its dismutase activity might lead to motor neuron degeneration, but a number ALS mutants have been shown to maintain a normal enzymatic activity (Xxxxxxxx et al., 1994). Moreover, analyses of transgenic mice that express mutant SOD1 have provided strong evidence that the toxicity is not via a loss of SOD1 activity (Xxxxxx and Cleveland, 1996). If loss of SOD1 activity was responsible for the observed ALS phenotype, then manipulating this activity would be predicted to alter disease onset and/or progression. However, crossing of mutant SOD1 mice with mice overexpressing wild-type SOD1 or in which the wild-type SOD1 gene has been ablated does not alter disease onset or progression (Bruijn et al., 1998). These results suggest that the toxicity of mutant SOD1 involves a novel toxic gain of function. The nature of this toxicity is still not clear but there is evidence for several mechanisms. These include oxidative damage, accumulation of intracellular aggregates, mitochondrial dysfunction, growth factor deficiency, astroglial cell pathology, glutamate excitotoxicity, ER stress and damage to axonal transport (see for review (Xxxxxxxxx, 2009)). Although SOD1 is ubiquitously expressed, its pathogenic effect was thought to occur strictly within motor neurons. This view was challenged by analyses of transgenic mice with mutant SOD1 expression restricted to neurons or astrocytes, which failed to develop disease (Xxxx et al., 2000; Xxxxxxxxxxx et al., 2001). Furthermore, pathogenic SOD1 expression in motor neurons surrounded by a wild-type environment prolonged ...