Macromolecular connectivity landscape of mammalian brain

Connectivity webs mediate the unique biology of mammalian brain. Yet while cell and gene circuit maps are increasing in resolution, knowledge of the molecular interaction networks of the brain is limited. Here, we applied multidimensional biochemical fractionation with precision mass spectrometry to survey endogenous macromolecules in adult mouse brain. We defined a global ‘interactome’ landscape consisting of hundreds of multi-protein complexes, most never reported before. Brain selective assemblies exhibit distinctive biophysical and functional attributes, including enrichment for synaptic, RNA-binding and other evolutionarily conserved proteins showing tissue-, regional- and cell-type specificity. Strikingly, many macromolecules have links to diverse neurological disorders and disease variants, illustrating the broad pathophysiological relevance of the network. We validated a putative 15-member complex associated with Amyotrophic Lateral Sclerosis using reciprocal pulldowns and a transgenic rodent model, establishing balancing functions in alternative splicing and disease progression. This resource facilitates exploration of the mechanistic basis of neuronal function, synaptic plasticity and diseases of the central nervous system.