Advanced glycation endproducts are deposited in neuronal hyaline inclusions: a study on familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation

• Published in: Acta neuropathologica Vol. 97; no. 3; pp. 240 - 246
• Main Authors: Shibata, N, Hirano, A, Kato, S, Nagai, R, Horiuchi, S, Komori, T, Umahara, T, Asayama, K, Kobayashi, M
• Format: Journal Article
• Language: English
• Published: Germany Springer Nature B.V 01-03-1999
• Subjects: Adult; Advanced glycosylation end products; Aged; Aged, 80 and over; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Antibodies; Cytoplasm; Degeneration; Female; Glycation End Products, Advanced - immunology; Glycation End Products, Advanced - metabolism; Glycosylation; Humans; Hyalin - metabolism; Immunoelectron microscopy; Immunohistochemistry; Inclusion Bodies - metabolism; Lipid peroxidation; Localization; Lysine; Lysine - analogs & derivatives; Lysine - immunology; Lysine - metabolism; Male; Microscopy, Immunoelectron; Middle Aged; Monoclonal antibodies; Motor neurons; Motor Neurons - metabolism; Mutation; Neurofilament Proteins - immunology; Neurofilament Proteins - metabolism; Neurofilaments; Oxidation; Oxidative stress; Spinal Cord - metabolism; Superoxide dismutase; Superoxide Dismutase - genetics; Superoxide Dismutase - immunology; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Ubiquitin; Ubiquitins - immunology; Ubiquitins - metabolism
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s004010050980

To determine the role of advanced glycation endproducts (AGE) in the pathogenesis of familial amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) mutation, we investigated the immunohistochemical localization of N(epsilon)-carboxymethyl-lysine (CML), one of the major AGE structures, in spinal cords from three familial ALS patients with a heterozygous Ala to Val substitution at codon 4 in the gene for SOD1. Neuronal hyaline inclusions (NHIs), the abnormal structures seen in some of the remaining lower motor neurons of familial ALS patients with SOD1 mutation, were intensely stained by a monoclonal antibody specific for CML in contrast to the only weakly stained cytoplasm. Immunoelectron microscopy depicted the CML determinants restricted to the granule-associated thick linear structures that mainly compose the NHIs. The NHIs were also recognized by antibodies to SOD1, phosphorylated neurofilament protein and ubiquitin. No focal collection of either CML or SOD1 was found in neurons of the control individuals. Our results indicate that CML is a component of the NHIs of familial ALS patients with SOD1 mutation, and suggest that the CML formation may be mediated by protein glycoxidation or lipid peroxidation in the presence of oxidative stress from mutant SOD1, in association with motor neuron degeneration.