Astrocytes viewed through the lens of their proteomes and subproteomes

Abstract

Astrocytes are morphologically complex and functionally diverse glial cells that play central roles in neural circuits and disease. Although transcriptomic and physiological analyses have advanced understanding of astrocyte function, the intricacies of the relationship between gene expression and protein levels remains poorly understood. Proteins, rather than transcripts, execute the molecular processes that define astrocyte function, often within specialized subcellular compartments whose molecular composition has remained largely unresolved. Recent advances with genetically encoded proximity-dependent biotinylation have enabled mapping of astrocyte proteomes and subproteomes, revealing the spatial organization of protein networks that underpin astrocyte identity and function. In this Review we summarize strategies for defining astrocyte proteomes and subproteomes, emphasizing methodological innovations that permit cell-type-specific and spatially resolved proteomic profiling within intact neural tissue. The use of these approaches is shaping understanding of astrocyte biology by uncovering the molecular nature of their distributed physiology and the molecular basis of their interactions with neurons and other cells. Viewing astrocytes through a proteomic lens is beginning to help elucidate the molecular determinants of their morphology, signalling, and roles in homeostasis and disease. Such insights should enable detailed mechanistic understanding of astrocyte function and identify new avenues for targeting astrocytic contributions to brain disorders. Recent technological advances have provided novel understanding of the spatiotemporal relationship between gene expression and protein levels. In this Review, Khakh and colleagues summarize recent work on astrocyte proteomes and subproteomes, emphasizing methodological breakthroughs and new biological insights relevant to fundamental astrocyte biology in neural circuits.