Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant

摘要: Abstract Mutations in superoxide dismutase 1 (SOD1; EC 1.15.1.1) are responsible for a proportion of familial amyotrophic lateral sclerosis (ALS) through acquisition an as-yet-unidentified toxic property or properties. Two proposed possibilities that toxicity may arise from imperfectly folded mutant SOD1 catalyzing the nitration tyrosines [Beckman, J. S., Carson, M., Smith, C. D. & Koppenol, W. H. (1993) Nature (London) 364, 584] use peroxynitrite peroxidation arising elevated production hydroxyl radicals hydrogen peroxide as substrate [Wiedau-Pazos, Goto, J., Rabizadeh, Gralla, E. D., Roe, A., Valentine, S. Bredesen, (1996) Science 271, 515–518]. To test these possibilities, levels nitrotyrosine and markers radical formation were measured two lines transgenic mice develop progressive motor neuron disease expressing human ALS-linked mutation G37R. Relative to normal high wild-type SOD1, 3-nitrotyrosine by 2- 3-fold spinal cords coincident with earliest pathological abnormalities remained cord throughout progression disease. However, no increases protein-bound found during any stage SOD1-mutant-mediated at end sporadic SOD1-mediated ALS. When salicylate trapping measurement malondialdehyde used, there was evidence enhanced lipid peroxidation, respectively. The presence beginning stages cellular pathology continuing demonstrates tyrosine is one vivo aberrant this mutant.