The cell-surface shared proteome of astrocytes and neurons and the molecular foundations of their multicellular interactions.

Neurons and astrocytes are predominant brain cells that extensively interact, but the molecular basis of their interactions remains largely unexplored. We identified and mapped striatal astrocytic and neuronal cell-surface proteins (CSPs) and found that many were shared, representing the cell-surface shared proteome of astrocytes and neurons (CS SPAN) bridging striatal astrocyte-neuron interaction sites. CS SPAN was replete with extracellular matrix proteins, cell adhesion molecules, transporters, ion channels, and G protein-coupled receptors. By mapping the cellular origins of astrocytic CSPs, we identified astrocytic interactions with diverse parenchymal cells. Broadly concordant with human data, in a mouse model of Huntington's disease (HD), pathophysiology and its genetic attenuation were accompanied by altered and restored CS SPAN and CSPs, respectively. CS SPAN also included molecules dysregulated in diverse brain disorders. Our study reveals the astrocyte-neuron interface in molecular terms and provides a mechanistic foundation for exploring its physiological roles and contributions to brain diseases.