The changing face of neurodegenerative research
Recent research published by a team from Heidelberg University has identified a number of molecules which may mitigate currently untreatable neurodegenerative diseases.
The findings, published in Science last month, revolve around the coupling of N-methyl-D-aspartate receptors (NMDAR) with a calcium-activated non-selective cation channel, TRPM4. Most previous attempts to use NMDAR antagonists to treat neurodegenerative diseases have failed due to the fact that, alongside their essential physiological role in synaptic plasticity and cognitive functions, NMDARs are also promotors of neuronal death. By initiating transcription shutoff pathways, NMDARs can lead to mitochondrial dysfunction and excitotoxic cell death. The molecular basis of this toxic NMDAR signalling is unknown, although a high intracellular calcium load has been implicated.
The researchers set out to see if it was possible to disentangle these two paradoxical properties of NMDARs. Their findings revealed that two NMDAR subunits – GluN2A and GluN2B – form a complex with TRPM4. This interaction is mediated by an amino acid intracellular domain of TRPM4, termed ‘TwinF’, which interacts with a stretch of amino acids known as I4, located within the intracellular near-membrane portion of GluN2A and GluN2B. This NMDAR/TRPM4 complex, it was hypothesized, lies at the root of NMDARs’ propensity for toxicity.
Thankfully, this complex can be disrupted by one of two ways, either:
- The expression of TwinF, which acts by competing with endogenous TRPM4 for binding to GluN2A and GluN2B
- Small-molecule NMDAR/TRPM4 interaction interface inhibitors
According to the researchers, both of these pathways provide “robust protection against excitotoxic cell death in cultured neurons and in vivo in mouse models of neurodegeneration.” They also eliminate the aforementioned excitotoxicity-associated transcription shutoff and mitochondrial dysfunction, all the while leaving synaptic and extrasynaptic NMDAR-mediated current and calcium signalling unaffected.
This is big news. The findings provide a new conceptual basis for therapeutic targeting of toxic NMDAR signalling, itself a contributor to many neurological conditions, including stroke, traumatic brain injury, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and retinal degeneration. As such, the implications of this research are far-reaching, and could lead to the development of therapeutics for a broad range of conditions.
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