A cross-vertebrate brain protein interaction map identifies conserved neural and non-neural complexes

Protein-protein interactions underlie core brain functions, including neurotransmitter release, receptor activation, and intracellular signaling. Here, we present a compendium of protein-protein interactions conserved across vertebrate brains, spanning over 300 million years of evolution. From 2,197 biochemical fractions across five vertebrate species, we identify over 81,000 high-confidence interactions among 6,108 conserved proteins. This interaction map (VerteBrain) reveals both regulatory and structural complexes, including extensive synaptonemal protein associations likely involved in inter-neuronal coordination. Conservation across species underscores essential roles in neuronal and glial function, as well as in additional tissues for more widely expressed complexes. The VerteBrain dataset uncovers candidate disease mechanisms, including roles for ARHGEF1 in short stature syndromes, synaptic vesicle trafficking complexes in epilepsy, and RELCH (Rab11-binding and LisH domain, coiled-coil and HEAT repeat-containing) in congenital deafness. VerteBrain provides a resource for investigating brain protein interactions and their relevance to human neurological disorders.