Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations

Hilmar Bading

doi:10.1084/jem.20161673

journal article Open Access Feb 16, 2017

Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations

Hilmar Bading

Journal of Experimental Medicine Vol. 214 No. 3 pp. 569-578 · Rockefeller University Press

View at Publisher Save 10.1084/jem.20161673

Abstract

Activation of extrasynaptic N-methyl-d-aspartate (NMDA) receptors causes neurodegeneration and cell death. The disease mechanism involves a pathological triad consisting of mitochondrial dysfunction, loss of integrity of neuronal structures and connectivity, and disruption of excitation–transcription coupling caused by CREB (cyclic adenosine monophosphate–responsive element-binding protein) shut-off and nuclear accumulation of class IIa histone deacetylases. Interdependency within the triad fuels an accelerating disease progression that culminates in failure of mitochondrial energy production and cell loss. Both acute and slowly progressive neurodegenerative conditions, including stroke, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease, share increased death signaling by extrasynaptic NMDA receptors caused by elevated extracellular glutamate concentrations or relocalization of NMDA receptors to extrasynaptic sites. Six areas of therapeutic objectives are defined, based on which a broadly applicable combination therapy is proposed to combat the pathological triad of extrasynaptic NMDA receptor signaling that is common to many neurodegenerative diseases.

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Metrics

140

Citations

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References

Details

Published: Feb 16, 2017
Vol/Issue: 214(3)
Pages: 569-578
License: View

Authors

H

Hilmar Bading

Department of Neurobiology, Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany

Funding

Deutsche Forschungsgemeinschaft

European Research Council Award: 233024

DFG

ERC Award: 640892

Cite This Article

Hilmar Bading (2017). Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations. Journal of Experimental Medicine, 214(3), 569-578. https://doi.org/10.1084/jem.20161673

Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations

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