Polyamines, such as spermidine, are essential regulators of brain development, yet how cells control their uptake and extracellular levels remains unclear. Here we show that ATP13A4, a transport protein enriched in glia and prominently expressed in astrocytes, governs brain polyamine balance. Using biochemical, cellular, and animal models, we find that ATP13A4 imports polyamines into cells and thereby limits their availability outside cells. Loss of ATP13A4 simplifies astrocyte morphology and increases the excitatory connections, or synapses, that astrocytes promote between neurons; adding spermidine reproduces these effects, identifying extracellular spermidine as a synapse-promoting signal. In mice lacking Atp13a4, brain polyamines are redistributed, with reduced levels in the cortex and accumulation in cerebrospinal fluid. This is accompanied by excess excitatory synapses, delayed early development, and mild, female-biased behavioral changes in adulthood. Rare ATP13A4 variants linked to neurodevelopmental disorders disrupt its function. Thus, astrocytic polyamine clearance via ATP13A4 tunes extracellular spermidine to shape synapse formation during development. Polyamines help shape brain development, but how brain extracellular levels are controlled has remained unclear. Here, the authors show that astrocytic ATP13A4 clears extracellular spermidine to regulate excitatory synapse formation and neurodevelopment.
S. van Veen, Emily Meeus, D. Irala et al.· Nature Communications· 1 citation
Glial cells, including radial glia, oligodendrocyte precursor cells (OPCs), oligodendrocytes, astrocytes, and microglia, are active and dynamic regulators of central nervous system (CNS) development, homeostasis, and disease. Through extensive interactions with neurons, other glial populations, and the vasculature, they form highly specialized communication networks that are essential for normal brain function. While transcriptomic approaches have revealed extensive glial heterogeneity and enabled the prediction of putative signaling networks, a critical challenge remains in validating and translating these findings at the level of distinct protein complexes existing both within and between the various glial cell types. This is largely due to the fact that traditional proteomic technologies lack spatial resolution and/or fail to capture protein interaction networks. Proximity labeling (PL) has emerged as a powerful strategy to overcome these limitations by enabling cell‐type‐specific mapping of protein networks and subcellular proteomes, with spatial and temporal precision. Emerging studies have applied PL enzymes, such as BioID, TurboID, and HRP, across diverse glial populations, starting to uncover protein networks supporting their interactions with neurons and vascular elements, allowing metabolic support, maintenance of microenvironment homeostasis and cell–cell communication (including synaptic modulation). In this review, we summarize the main PL enzymes, discuss key studies across different glial cell types, and examine the technical challenges and future perspectives of applying PL to investigate glial biology. By complementing transcriptomic data with spatially resolved proteomic insights, PL provides a unique opportunity to deepen our understanding of glial cell biology in health and disease.
João Baltar, R. Abati, L. Florido et al.· Glia· 0 citations
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