Yan J, Bengtson CP, Buchthal B, Hagenston AM, Bading H.
Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants.
Science. 2020 Oct 9;370(6513)
PubMed.
This is a fascinating and elegant study, opening up a new potential therapeutic pathway to treat neurologic diseases that manifest extrasynaptic NMDAR hyperactivity—including AD. The Bading approach allows us to potentially intervene at a downstream event, TRPM4 channel activity, with important therapeutic implications. I think it is a fantastic study and hope to learn more about this pathway in the near future from Hilmar Bading and his colleagues.
Downstream of dysfunctional astrocytes in AD, one process that loss of glutamate homeostasis may converge on is excitotoxic neuronal and synapse loss. Deficits in glutamate uptake capacity due to glutamate transporter hypo-expression, bioenergetic deficits associated with vascular impairments, and Aβ exposure to astrocytes can all lead to elevate ambient glutamate and activation of extrasynaptic NMDARs. Bading’s lab found years ago that these receptors seem particularly adept at coupling to pro-death pathways compared to synaptic ones, something recapitulated and built on in other disease models by the likes of Stuart Lipton, Lynn Raymond and Michael Kreutz. However, the molecular basis for this has eluded researchers till now. The uncoupling of NMDARs from TRPM4 has the potential for being the Holy Grail of allowing physiological NMDAR signaling while preventing the pathological consequences of extrasynaptic NMDAR activation. An exciting discovery, and we can hope that such approaches can influence chronic neurodegenerative disease trajectory.
Comments
Sanford-Burnham Institute for Medical Research
This is a fascinating and elegant study, opening up a new potential therapeutic pathway to treat neurologic diseases that manifest extrasynaptic NMDAR hyperactivity—including AD. The Bading approach allows us to potentially intervene at a downstream event, TRPM4 channel activity, with important therapeutic implications. I think it is a fantastic study and hope to learn more about this pathway in the near future from Hilmar Bading and his colleagues.
View all comments by Stuart A. LiptonUniversity of Edinburgh
Downstream of dysfunctional astrocytes in AD, one process that loss of glutamate homeostasis may converge on is excitotoxic neuronal and synapse loss. Deficits in glutamate uptake capacity due to glutamate transporter hypo-expression, bioenergetic deficits associated with vascular impairments, and Aβ exposure to astrocytes can all lead to elevate ambient glutamate and activation of extrasynaptic NMDARs. Bading’s lab found years ago that these receptors seem particularly adept at coupling to pro-death pathways compared to synaptic ones, something recapitulated and built on in other disease models by the likes of Stuart Lipton, Lynn Raymond and Michael Kreutz. However, the molecular basis for this has eluded researchers till now. The uncoupling of NMDARs from TRPM4 has the potential for being the Holy Grail of allowing physiological NMDAR signaling while preventing the pathological consequences of extrasynaptic NMDAR activation. An exciting discovery, and we can hope that such approaches can influence chronic neurodegenerative disease trajectory.
View all comments by Giles HardinghamMake a Comment
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