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The Lipid Peroxidation Product 4-Hydroxynonenal Impairs Glutamate and Glucose Transport and Choline Acetyltransferase Activity in NSC-19 Motor Neuron Cells

https://doi.org/10.1006/exnr.1998.6890Get rights and content

Abstract

Both oxidative stress and excitotoxicity are implicated in the pathogenesis of a number of neurodegenerative disorders, such as amyotrophic lateral sclerosis. We previously reported increased modification of proteins by 4-hydroxynonenal (HNE), a product of membrane lipid peroxidation, in the spinal cords of patients with amyotrophic lateral sclerosis relative to controls. In the current study, we examined the functional consequences of protein modification by HNE in a cell line with a motor neuron phenotype, NSC-19. Treatment of NSC-19 cells with FeSO4, which catalyzes lipid peroxidation, or HNE induced concentration-dependent decreases in glucose and glutamate transport. Vitamin E and propyl gallate blocked the impairment of glucose and glutamate transport caused by FeSO4in these cells, but not that caused by HNE, whereas glutathione blocked the effects of FeSO4as well as HNE. Both FeSO4and HNE caused an increase in the number of apoptotic nuclei in NSC-19 cultures, but this occurred subsequent to the impairment of glucose and glutamate transport. Reductions in choline acetyltransferase activity were also observed in FeSO4- or HNE-treated NSC-19 cells before induction of apoptosis. Our results suggest that, prior to cell death, oxidative stress and HNE down-regulate cholinergic markers and impair glucose and glutamate transport in motor neurons, the latter of which may lead to excitotoxic degeneration of the cells.

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      Aggregation and accumulation of the mutant SOD1 occurs in the motor neurons of anterior horns in fALS patients in the form of hyaline inclusions, which contain epitopes of ubiquitin and phosphorylated neurofilaments [76]. An in vitro study showed that HNE impairs the glutamate and glucose transport and the choline acetyltransferase activity in cultured motor neurons [77], while human autopsy materials have shown increased levels of HNE, which modifies astrocytic glutamate transporter EAAT2 impairing glutamate transport in ALS. In sALS patients HNE was found to be increased in spinal motor neurons of the ventral horn [78], in which strong immunoreactivity for HNE adducts with epsilon-n-carboxymethyl lysine present in the cytoplasm of the degenerated motor neurons suggests involvement of HNE in ALS, while acrolein was not detected in the spinal cord of ALS patients [79].

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