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<p>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.</p>

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ATP13A4 gates extracellular polyamine levels to control excitatory synaptogenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Sarah van Veen,
  • Emily Meeus,
  • Dolores Irala,
  • Kristina Sakers,
  • Zhaolin Liu,
  • Justin Savage,
  • Gabrielle Séjourné,
  • Dhanesh Sivadasan Bindu,
  • Elke Ausloos,
  • Hanna Elzbieta Grzesik,
  • Hanne Dhondt,
  • Nina Schoonvliet,
  • Chris Van den Haute,
  • Joris Van Asselberghs,
  • Marta Montpeyó Garcia-Moreno,
  • Keimpe Wierda,
  • Veerle Baekelandt,
  • Konrad Platzer,
  • Kevin Rostasy,
  • Kai Lee Yap,
  • Jan Eggermont,
  • Matthew G. Holt,
  • Cagla Eroglu,
  • Peter Vangheluwe

摘要

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.