Proteome analyses of the postsynaptic density (PSD), a specialized region beneath the postsynaptic membrane of excitatory synapses, have identified several thousand proteins. While proteins with predictable functions have been well studied, functionally uncharacterized proteins are mostly overlooked. In this study, Kaizuka et al. conducted a comprehensive meta-analysis of 35 PSD proteome datasets, encompassing a total of 5,869 proteins. Employing a ranking methodology, they identified 97 proteins that remain inadequately characterized. From this selection, they focused more detailed analysis on the highest-ranked protein, FAM81A, finding that it interacts with PSD proteins, including PSD-95, SynGAP, and NMDA receptors, and promotes liquid–liquid phase separation of those proteins in cultured cells or in vitro. Down-regulation of FAM81A in cultured neurons causes a decrease in the size of PSD-95 puncta and the frequency of neuronal firing, suggesting that FAM81A plays a crucial role in facilitating the interaction and assembly of proteins within the PSD, and its presence is important for maintaining normal synaptic function. This image shows FAM81A-GFP (green) co-expressed with PSD-95-mCherry (red) and BFP (blue) in mouse hippocampal neurons. Droplets composed of coincident FAM81A and PSD-95 (white) can be seen at the tips of dendritic spines and within the cytoplasm.

Image Credit: Takeshi Kaizuka