Advanced glycation endproducts are deposited in neuronal hyaline inclusions: a study on familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation.
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.
Shibata
N
N
Department of Pathology, Tokyo Women's Medical College, Japan.
Hirano
A
A
Kato
S
S
Nagai
R
R
Horiuchi
S
S
Komori
T
T
Umahara
T
T
Asayama
K
K
Kobayashi
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000906:Antibodies; D005260:Female; D017127:Glycation End Products, Advanced / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006818:Hyalin / Q000378:metabolism*; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism*; D008239:Lysine / Q000031:analogs & derivatives / Q000276:immunology / Q000378:metabolism; D008297:Male; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism*; D016900:Neurofilament Proteins / Q000276:immunology / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014452:Ubiquitins / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D017127:Glycation End Products, Advanced; D016900:Neurofilament Proteins; C000606290:SOD1 protein, human; D014452:Ubiquitins; C048496:N(6)-carboxymethyllysine; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D008239:Lysine