Nonoxidative protein glycation is implicated in familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation

Abstract

To assess a role for oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS), we analyzed the immunohistochemical localization of 8-hydroxy2'-deoxyguanosine (OHdG) as a nucleic acid oxidation product, acrolein-protein adduct and 4-hydroxy-2-nonenal (HNE)-protein adduct as lipid peroxidation products, Nepsiloncarboxymethyl-lysine (CML) as a lipid peroxidation or protein glycoxidation product, pentosidine as a protein glycoxidation product, and imidazolone and pyrraline as nonoxidative protein glycation products in the spinal cord of three familial ALS patients with superoxide dismutase(SOD 1) A4V mutation, six sporadic ALS patients, and six age-matched control individuals. The spinal cord sections of the control cases did not show any distinct immunoreactivities for these examined products. In the familial ALS cases, intense immunoreactivities for pyrraline and CML were confined to the characteristic Lewy body-like hyaline inclusions, and imidazolone immunoreactivity was located in the cytoplasm of the residual motor neurons. No significant immunoreactivities for other examined products were detected in the familial ALS spinal cords. In the sporadic ALS cases, intense immunoreactivities for pentosidine, CML and HNE-protein adduct were seen in the cytoplasm of the degenerated motor neurons, and OHdG immunoreactivity was located in the cell nuclei of the residual neurons and glial cells. The present results indicate that oxidative reactions are involved in the disease processes of sporadic ALS, while there is no evidence for increased oxidative damage except for CML deposition in the familial ALS spinal cords. Furthermore, it is likely that the accumulation of pyrraline and imidazolone supports a nonoxidative mechanism in SOD1-related motor neuron degeneration.

Superoxide dismutase-1 mutation-related neurotoxicity in familial amyotrophic lateral sclerosis

“…138,139 Furthermore, in familial ALS patients with A4V mutation, the concentration of 8-hydroxy-29 -deoxyguanosine (OHdG), the oxidation product of DNA via hydroxylation at the C-8 position, is not elevated but rather decreased in the motor cortex, 140 and no signi cant OHdG immunoreactivity is detected in the anterior horn cells. 141 These ndings form a striking contrast to evidence that sporadic ALS patients show elevated OHdG concentration in the motor cortex and spinal cord 140,142 and intense OHdG immunoreactivity in the anterior horn cells. 140,141 Therapeutic trials with an antioxidant N-acetyl cysteine do not result in prolonged survival of G93A transgenic mice or sporadic ALS patients.…”

Oxidative stress in brain aging, neurodegenerative and vascular diseases: An overview

“…Analyzing SALS spinal cords, it was found immunoreactivity to HNE-histidine and crotonaldehyde-lysine, indicative of lipid peroxidation; carboxymethyl-lysine (CML), indicative of lipid peroxidation or protein glycoxidation; and pentosidine, indicative of protein glycoxidation [120]. In an other study it was also found that the pattern of immunoreactivity in FALS spinal cord was quite different, with intense immunoreactivity for CML bit also for pyrraline, marker of non oxidative protein glication, and in the Lewy body-like inclusion only and imidazolone -another marker of non oxidative protein glication -immunoreactivity in the cytoplasm of the residual motor neurons [121].…”

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

“…A recent study (54) demonstrated that LTB 4 12HD was effective at reducing a wide variety of cytotoxic ␣,␤-unsaturated aldehydes and ketones including products of lipid peroxidation such as 4-hydroxy-2-nonenal (HNE). HNE has been shown to be elevated in the cerebrospinal fluid of SALS cases (55) and SALS spinal cord (56,57). A potential chemoprotective role for the enzyme was suggested by its ability to confer resistance of LTB 4 12HD-transfected cell lines to HNE-induced apoptosis (54).…”