Advanced glycation endproducts in neurofilament conglomeration of motoneurons in familial and sporadic amyotrophic lateral sclerosis.
BACKGROUND
Massive neurofilament conglomeration in motor neurons has been described to occur in the early stages of both familial and sporadic amyotrophic lateral sclerosis (ALS). Previously, neurofilament conglomerates were immunolabeled for both superoxide dismutase (SOD1) and nitrotyrosine, suggesting the potential for oxidative nitration damage to neurofilament protein by peroxynitrite. Long-lived neurofilaments may also undergo modification by advanced glycation endproducts (AGEs) with concomitant generation of free radicals, including superoxide. This radical species may then react with nitric oxide to form the potent oxidant, peroxynitrite, which in turn can nitrate neurofilament protein. Such a glycated and nitrated neurofilament protein may become resistant to proteolytic systems, forming high-molecular-weight protein complexes and cytotoxic, neuronal inclusions.


METHODS
Paraffin sections containing both neurofilament conglomerates and neuronal inclusions were obtained from patients with sporadic (n = 5) and familial (n = 2) ALS and were probed with specific antibodies directed against the AGEs cypentodine/piperidine-enolone, arginine-lysine imidazole, pentosidine, and pyrraline.


RESULTS
Neurofilament conglomerates, but not neuronal inclusions, were intensely immunolabeled with each of the anti-AGE antibodies tested. The immunoreactivity was selective for neurofilament conglomerates and suggested that AGEs may form inter- or intramolecular cross-links in neurofilament proteins.


CONCLUSIONS
These data support the hypothesis that AGE formation affects neurofilament proteins in vivo and is associated with the concomitant induction of SODI and protein nitration in neurofilament conglomerates. AGE formation in neurofilament protein may not only cause covalent cross-linking but also generate superoxide and block nitric oxide-mediated responses, thereby perpetuating neuronal toxicity in patients with ALS.
Chou
S M
SM
F. Norris ALS/MDA Research Center, California Pacific Medical Center, San Francisco 94115, USA. schou@cooper.cpmc.org
Wang
H S
HS
Taniguchi
A
A
Bucala
R
R
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001923:Brain Chemistry; D017127:Glycation End Products, Advanced / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D009046:Motor Neurons / Q000378:metabolism*; D016900:Neurofilament Proteins / Q000032:analysis*; D013116:Spinal Cord / Q000737:chemistry
D017127:Glycation End Products, Advanced; D016900:Neurofilament Proteins