SODls

To test whether increasing or decreasing SOD1 has an impact on disease in the mutant SOD1 mice, these animals were mated with wild-type SOD1 or SODl mice. 

Bruijn, L. I., Becher, M. W., Lee, M. K. etal. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SODl-contain-ing inclusions. Neuron 18 327-338,1997. 

Niwa, j., et al., Dorfin ubiquitylates mutant SODl and prevents mutant... 

SODl-mediated neurotoxicity. J Biol Chem, 2002, 277f39J, 36793-8. 

Watanabe, M., et al., Histological evidence of protein aggregation in mutant SODl transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol Dis, 2001, 8f6J, 933-41. 

Takeuchi, H., et ah, Hsp70 and Hsp40 improve neurite outgrowth and suppress intracytoplasmic aggregate formation in cultured neuronal cells expressing mutant SODl. Brain Res, 2002, 949(1-2), 11-22. 

Supportive evidence comes from a study showing that intraventricular administration of z-VADfluoromethylketone (fmk), a pan-caspase inhibitor increases the lifespan of SODl transgenic mice by approximately 25% (Li et al, 2000). Furthermore, overexpression of XIAP, a mammalian inhibitor of caspases 3,7 and 9, in spinal motor neurons of mutant SODl mice attenuated disease progression without delaying onset, whilst expression of p35, a baculoviral caspase inhibitor that does not inhibit caspase-9, delayed onset without decreasing disease progression (Inoue et al, 2003). Moreover, caspase-9 was activated in spinal motor neurons of ALS patients. 

Strain J, Lorenz CR, Bode J, et al. 1998. Supressors of superoxide dismutase (SODl) deficiency in Saccharomyces cerevisiae. Identification of proteins predicted to mediate iron-sulfur cluster assembly. J Biol Chem 273 31138-44. 

Wooley, C. M., Sher, R. B., Kale, A., Frankel, W. N., Cox, G. A. and Seburn, K. L. (2005) Gait analysis detects early changes in transgenic SODl(G93A) mice. Muscle Nerve 32, 43-50. 

Fig. 9. Copper activation of Acel induces expression of three genes in Saccharo-myces cerevisiae. Crs5 and Cupl encode metallothionein-like molecules that buffer the cytoplasmic Cu concentration. Sodl is a Cu-buffering molecule in addition to its role as a superoxide dismutase.

Fig. 11. Multiple sequence alignment of the copper chaperones for SODl using the CLUSTAL method (see text) (Higgins and Sharp, 1989). Sequence numbering corresponds to that of the yeast protein. Domain 1 cysteine residues believed to be important in uptake under copper-limiting conditions and domain 3 cysteine residues believed to be important in copper delivery to SOD 1 are boxed in black and labeled with asterisks. Residues in domain 2 that correspond to copper and zinc ligands in yeast and human SODl are boxed in black. Residues in domain 2 postulated to be involved in SODl target recognition (Trp-183 and Arg-217) are boxed in black and labeled with asterisks. The vertical arrows underneath domain 2 represent the positions of cysteine residues that make the disulhde bond in yeast and human SODl.

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