Macromolecular Connectivity Landscape of Mammalian Brain

Connectivity webs mediate the unique biology of the mammalian brain. Yet while cell circuit maps are increasingly available, knowledge of the underlying molecular networks remains limited. Here, we applied multi-dimensional biochemical fractionation with precision mass spectrometry and machine learning to survey endogenous macromolecules in adult mouse brain. We defined a global ‘interactome’ of multi-protein complexes, most never reported before. These brain-selective assemblies have distinct physical and functional attributes and show regional- and cell-type specificity. A striking number are also linked to neurological disorders and disease variants with broad pathophysiological relevance. Using reciprocal pulldowns and a transgenic model, we validated a putative 15-member RNA-binding protein complex associated with amyotrophic lateral sclerosis, establishing regulatory functions in alternative splicing and disease progression. This Brain Interaction Map – or BraInMap – resource facilitates mechanistic exploration of the molecular machinery driving core processes and diseases of the central nervous system.