Innovative Molecular Approach Offers New Hope for Fragile X Syndrome Treatment, Study shows
Building on more than two decades of research, a study by MIT neuroscientists at The Picower Institute for Learning and Memory reports a new way to treat pathology and symptoms of fragile X syndrome, the most common genetically-caused autism spectrum disorder. The team showed that augmenting a novel type of neurotransmitter signaling reduced hallmarks of fragile X in mouse models of the disorder.
The new approach described in Cell Reports works by targeting a specific molecular subunit of “NMDA” receptors that they discovered plays a key role in how neurons synthesize proteins to regulate their connections, or “synapses,” with other neurons in brain circuits. The scientists showed that in fragile X model mice, increasing the receptor’s activity caused neurons in the hippocampus region of the brain to increase molecular signaling that suppressed excessive bulk protein synthesis, leading to other key improvements
“One of the things I find most satisfying about this study is that the pieces of the puzzle fit so nicely into what had come before,” said study senior author Mark Bear, Picower Professor in MIT’s Department of Brain and Cognitive Sciences. Former postdoc Stephanie Barnes, now a lecturer at the University of Glasgow, is the study’s lead author. Bear’s lab showed that fragile X and another autism disorder, tuberous sclerosis (Tsc), represented two ends of a continuum of a kind of protein synthesis in the same neurons. In fragile X there was too much. In Tsc there was too little. When lab members crossbred fragile X and Tsc mice, in fact, their offspring emerged healthy as the mutations of each disorder essentially canceled each other out.
For Bear and Barnes these studies raised the prospect that if they could pinpoint how NMDA receptors affect protein synthesis they might identify a new mechanism that could be manipulated therapeutically to address fragile X (and perhaps tuberous sclerosis) pathology and symptoms.
The team now hypothesizes, based on another prior study in the lab, that the beneficial effect to fragile X mice of the 2B subunit’s CTD signaling is that it shifts the balance of protein synthesis away from an all-too-efficient translation of short messenger RNAs (which leads to excessive bulk protein synthesis) toward a lower efficiency translation of longer messenger RNAs.
Ref: Stephanie A. Barnes, Aurore Thomazeau, Peter S.B. Finnie. Non-ionotropic signaling through the NMDA receptor GluN2B carboxy-terminal domain drives dendritic spine plasticity and reverses fragile X phenotypes, Cell Reports: DOI: 10.1016/j.celrep.2025.115311
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