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.