Mimicking FUS hypomethylation preferentially weakens excitatory synapses via AMPA and NMDA-receptor dysregulation
Abstract
Abnormal methylation of the RNA-binding protein fused in sarcoma (FUS) has been implicated in frontotemporal lobar degeneration. Interestingly, hypomethylation has been shown to alter the biophysical interactions between FUS molecules, leading to liquid-liquid phase separation (LLPS) and the formation of irreversible condensates. Importantly, these hypomethylated FUS condensates are observed in patient postmortem tissue and are known to disrupt synapse function in animal models. However, the extent to which FUS hypomethylation impacts specific excitatory receptor classes remains unclear. Here, we use the FUS-16R hypomethylation mimic to uncover the progression of FUS pathophysiology at excitatory synapses. We found that mimicking hypomethylation of FUS and the subsequent aberrant cytosolic LLPS drive preferential synaptic dysfunction of AMPA and NMDA ionotropic glutamate receptors. In contrast, FUS hypomethylation did not impair metabotropic glutamate receptor 1/5 (mGluR1/5) or acetylcholine receptor (AChR) function. Collectively, these findings reveal a previously unknown selectivity of FUS hypomethylation-mediated pathophysiology on excitatory synapses in the hippocampus.
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BibTeX
@article{toneva2026mimicking,
title = {{Mimicking FUS hypomethylation preferentially weakens excitatory synapses via AMPA and NMDA-receptor dysregulation}},
author = {Margarita Toneva and Fanbo Kong and Siwon Oh and Seung-Chan Kim and Peter St George-Hyslop and Scott J. Mitchell and Kwangwook Cho},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-72173-y},
url = {https://www.nature.com/articles/s41598-026-72173-y},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mimicking FUS hypomethylation preferentially weakens excitatory synapses via AMPA and NMDA-receptor dysregulation
AU - Margarita Toneva
AU - Fanbo Kong
AU - Siwon Oh
AU - Seung-Chan Kim
AU - Peter St George-Hyslop
AU - Scott J. Mitchell
AU - Kwangwook Cho
PY - 2026
DA - 2026/10/03
JO - Scientific Reports
DO - 10.1038/s41598-026-72173-y
UR - https://www.nature.com/articles/s41598-026-72173-y
AB - Abnormal methylation of the RNA-binding protein fused in sarcoma (FUS) has been implicated in frontotemporal lobar degeneration. Interestingly, hypomethylation has been shown to alter the biophysical interactions between FUS molecules, leading to liquid-liquid phase separation (LLPS) and the formation of irreversible condensates. Importantly, these hypomethylated FUS condensates are observed in patient postmortem tissue and are known to disrupt synapse function in animal models. However, the extent to which FUS hypomethylation impacts specific excitatory receptor classes remains unclear. Here, we use the FUS-16R hypomethylation mimic to uncover the progression of FUS pathophysiology at excitatory synapses. We found that mimicking hypomethylation of FUS and the subsequent aberrant cytosolic LLPS drive preferential synaptic dysfunction of AMPA and NMDA ionotropic glutamate receptors. In contrast, FUS hypomethylation did not impair metabotropic glutamate receptor 1/5 (mGluR1/5) or acetylcholine receptor (AChR) function. Collectively, these findings reveal a previously unknown selectivity of FUS hypomethylation-mediated pathophysiology on excitatory synapses in the hippocampus.
SN - 2045-2322
ER -