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Advanced Glycation Endproducts in Neurofilament Conglomeration of Motoneurons in Familial and Sporadic Amyotrophic Lateral Sclerosis

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Abstract

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 end-products (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.

Materials and 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/piper-idine-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 SOD1 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.

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Acknowledgements

The authors gratefully acknowledge the generous contribution of antibodies against pyrraline and pentosidine by Drs. V. Monnier, G. Perry, and M. Smith of the Case Western Reserve University, Cleveland, Ohio.

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Authors and Affiliations

  1. F. Norris ALS/MDA Research Center, California Pacific Medical Center, 2351 Clay Street, Suite 416, San Francisco, California, 94115, USA

    Samuel M. Chou & Helen S. Wang

  2. Department of Neurology, Mie University School of Medicine, Tsu City, Japan

    Akira Taniguchi

  3. Laboratory of Medical Biochemistry, The Picower Institute for Medical Research, Manhasset, New York, USA

    Richard Bucala

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  1. Samuel M. Chou
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Correspondence to Samuel M. Chou.

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Communicated by R. Bucala.

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Chou, S.M., Wang, H.S., Taniguchi, A. et al. Advanced Glycation Endproducts in Neurofilament Conglomeration of Motoneurons in Familial and Sporadic Amyotrophic Lateral Sclerosis. Mol Med 4, 324–332 (1998). https://doi.org/10.1007/BF03401739

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