Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease.

Bourgognon, J.-M. , Spiers, J. G., Robinson, S. W., Scheiblich, H., Glynn, P., Ortori, C., Bradley, S. J. , Tobin, A. B. and Steinert, J. R. (2021) Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease. Proceedings of the National Academy of Sciences of the United States of America, 118(10), e200957911. (doi: 10.1073/pnas.2009579118) (PMID:33653950)

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Abstract

Several neurodegenerative diseases associated with protein misfolding (Alzheimer's and Parkinson's disease) exhibit oxidative and nitrergic stress following initiation of neuroinflammatory pathways. Associated nitric oxide (NO)-mediated posttranslational modifications impact upon protein functions that can exacerbate pathology. Nonenzymatic and irreversible glycation signaling has been implicated as an underlying pathway that promotes protein misfolding, but the direct interactions between both pathways are poorly understood. Here we investigated the therapeutic potential of pharmacologically suppressing neuroinflammatory NO signaling during early disease progression of prion-infected mice. Mice were injected daily with an NO synthase (NOS) inhibitor at early disease stages, hippocampal gene and protein expression levels of oxidative and nitrergic stress markers were analyzed, and electrophysiological characterization of pyramidal CA1 neurons was performed. Increased neuroinflammatory signaling was observed in mice between 6 and 10 wk postinoculation (w.p.i.) with scrapie prion protein. Their hippocampi were characterized by enhanced nitrergic stress associated with a decline in neuronal function by 9 w.p.i. Daily in vivo administration of the NOS inhibitor L-NAME between 6 and 9 w.p.i. at 20 mg/kg prevented the functional degeneration of hippocampal neurons in prion-diseased mice. We further found that this intervention in diseased mice reduced 3-nitrotyrosination of triose-phosphate isomerase, an enzyme involved in the formation of disease-associated glycation. Furthermore, L-NAME application led to a reduced expression of the receptor for advanced glycation end-products and the diminished accumulation of hippocampal prion misfolding. Our data suggest that suppressing neuroinflammatory NO signaling slows functional neurodegeneration and reduces nitrergic and glycation-associated cellular stress.

Item Type:Articles
Keywords:Glycation, neurodegeneration, neuroinflammation, nitric oxide, prion aggregation.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tobin, Andrew and Bourgognon, Dr Julie-Myrtille and Bradley, Dr Sophie
Authors: Bourgognon, J.-M., Spiers, J. G., Robinson, S. W., Scheiblich, H., Glynn, P., Ortori, C., Bradley, S. J., Tobin, A. B., and Steinert, J. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in 118(10):e200957911
Publisher Policy:Reproduced under a Creative Commons licence

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