Increased 3‐nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis

Abstract

The pathogenesis of neuronal degeneration in both sporadic and familial amyotrophic lateral sclerosis (ALS) associated with mutations in superoxide dismutase may involve oxidative stress. A leading candidate as a mediator of oxidative stress is peroxynitrite, which is formed by the reaction of superoxide with nitric oxide. 3-Nitrotyrosine is a relatively specific marker for oxidative damage mediated by peroxynitrite. In the present study, biochemical measurements showed increased concentrations of 3-nitrotyrosine and 3-nitro-4-hydroxyphenylacetic acid in the lumbar and thoracic spinal cord of ALS patients. Increased 3-nitrotyrosine immunoreactivity was observed in motor neurons of both sporadic and familial ALS patients. Neurologic control patients with cerebral ischemia also showed increased 3-nitrotyrosine immunoreactivity. These findings suggest that peroxynitrite-mediated oxidative damage may play a role in the pathogenesis of both sporadic and familial ALS.

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.…”

Low expression of human tubulin tyrosine ligase and suppressed tubulin tyrosination/detyrosination cycle are associated with impaired neuronal differentiation in neuroblastomas with poor prognosis

“…Therefore, whether nitrotyrosinated tubulin is harmful or not is still controversial. Nevertheless, as increased nitrotyrosination is reported in Alzheimer's disease and amyotrophic lateral sclerosis, [35][36][37] the functional analysis of the role of hTTL and tubulin tyrosination/detyrosination cycle should be important for understanding the pathogenesis of these disease. The treatment of cells with methylmercury (MeHg) is also reported to induce perturbation of cellular activities associated with the tubulin/microtubule system by altering the status of tubulin tyrosination in the rat FIGURE 5 -Expression of hTTL mRNA is associated with unfavorable prognosis of neuroblastoma.…”

Proteomic analysis of protein nitration in rat cerebellum: effect of biological aging

“…Increasing evidence shows that the age-related accumulation of oxidative modifications on brain proteins can alter neuronal function and increase the risk for neurodegenerative disorders (Hensley et al 1995;Shaw et al 1995;Alam et al 1997;Beal et al 1997;Castegna et al 2002Castegna et al , 2003. The ageassociated loss of specific motor and cognitive functions, paralleled by a region-specific accumulation of oxidative protein modifications emphasizes the critical role of such modifications in the brain (Forster et al 1996).…”