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

Abstract

Biochemistry. In the article "Cloning of the cDNA for the TATA-binding protein-associated factor II 170 subunit of transcription factor B-TFIID reveals homology to global transcription regulators in yeast and Drosophila" by Jan A. van der Knaap, Jan Willem Borst, Peter C. van der Vliet, Reiner Gentz, and H. Th. Marc Timmers, which appeared in number 22, October 28, 1997, of Proc. Natl. Acad. Sci. USA (94, 11827-11832), the following correction should be noted.Recently, we described cloning of the cDNA encoding the TAF II 170 subunit of B-TFIID transcription factor (Proc. Natl. Acad. Sci. USA, 94, 11827-11832 Communicated by Elaine V. Fuchs, University of Chicago, Chicago, IL, May 15, 1997 (received for review March 31, 1997 To test these possibilities, levels of nitrotyrosine and markers for hydroxyl radical formation were measured in two lines of transgenic mice that develop progressive motor neuron disease from expressing human familial ALS-linked SOD1 mutation G37R. Relative to normal mice or mice expressing high levels of wild-type human SOD1, 3-nitrotyrosine levels were elevated by 2-to 3-fold in spinal cords coincident with the earliest pathological abnormalities and remained elevated in spinal cord throughout progression of disease. However, no increases in protein-bound nitrotyrosine were found during any stage of SOD1-mutant-mediated disease in mice or at end stage of sporadic or SOD1-mediated familial human ALS. When salicylate trapping of hydroxyl radicals and measurement of levels of malondialdehyde were used, there was no evidence throughout disease progression in mice for enhanced production of hydroxyl radicals or lipid peroxidation, respectively. The presence of elevated nitrotyrosine levels beginning at the earliest stages of cellular pathology and continuing throughout progression of disease demonstrates that tyrosine nitration is one in vivo aberrant property of this ALS-linked SOD1 mutant. ABSTRACT

Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase

“…One hypothesis is that the Cu bound to mutant SOD1 plays a key role in generating the toxic property in SOD1-linked FALS, i.e., mutations induce conformational changes in SOD1 to facilitate the interactions of the catalytic Cu with small molecules such as peroxynitrite (12) or hydrogen peroxide (24) to generate toxic free radicals that damage a variety of cell constituents important for the maintenance and survival of motor neurons. Consistent with this view are results showing increased levels of free nitrotyrosine in G37R mutant SOD1 transgenic mice (25) and in both sporadic and familial ALS (26,27), as well as the demonstration that the glutamate transporter, GLT1, is inactivated by oxidative reactions initiated by hydrogen peroxide and catalyzed by FALS-linked mutant SOD1 (28). However, no experimental proof for these aberrant Cu chemistries, proposed to be central to the pathogenesis of FALS, has yet been established.…”

Analysis of the Cytosolic Proteome in a Cell Culture Model of Familial Amyotrophic Lateral Sclerosis Reveals Alterations to the Proteasome, Antioxidant Defenses, and Nitric Oxide Synthetic Pathways

“…However, the relevance of our findings here to ALS is reinforced by studies reporting nNOS up-regulation in human ALS cases (40,49) and inducible NOS up-regulation in transgenic mice expressing ALS hSOD1 mutants (50). Furthermore, increased levels of nitrotyrosine have been shown in human cerebrospinal fluid in sporadic ALS (SALS) (51) as well the spinal cord of a transgenic mouse model (15). We anticipate that exploitation of recently developed "nitroproteomic" techniques (52,53) will eventually clarify the contribution of altered nitric oxide metabolism to ALS.…”

“…Several studies have provided evidence for the role of peroxynitrite and nitric oxide in SOD1-related ALS. Increased nitrosylation of proteins by peroxynitrite has been suggested by elevated levels of 3-nitrotyrosine in transgenic mutant SOD1 mice (15,16). Reduced zinc binding has been demonstrated for several SOD1 mutants (17).…”

Protein Nitration in a Mouse Model of Familial Amyotrophic Lateral Sclerosis

“…Among these markers, nitrotyrosine (NT) has attracted attention in view of Beckman's theory, which suggests a greater propensity of SOD1 mutants to use peroxynitrite as an enzyme substrate, leading to tyrosine nitration (7). In fact, increased levels of free NT have been found in human patients and mouse models of ALS (6,8,9). However, in only very few studies has protein-bound NT been specifically characterized in connection with ALS.…”