Phospholipid-flippase chaperone CDC50A is required for synapse maintenance by regulating phosphatidylserine exposure

EMBO J. 2021 Nov 2;40(21):e107915. doi: 10.15252/embj.2021107915. Epub 2021 Sep 29.

Abstract

Synaptic refinement is a critical physiological process that removes excess synapses to establish and maintain functional neuronal circuits. Recent studies have shown that focal exposure of phosphatidylserine (PS) on synapses acts as an "eat me" signal to mediate synaptic pruning. However, the molecular mechanism underlying PS externalization at synapses remains elusive. Here, we find that murine CDC50A, a chaperone of phospholipid flippases, localizes to synapses, and that its expression depends on neuronal activity. Cdc50a knockdown leads to phosphatidylserine exposure at synapses and subsequent erroneous synapse removal by microglia partly via the GPR56 pathway. Taken together, our data support that CDC50A safeguards synapse maintenance by regulating focal phosphatidylserine exposure at synapses.

Keywords: CDC50A; GPR56; microglia; phosphatidylserine; synapse elimination.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Gene Expression Regulation
  • Genes, Reporter
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / cytology
  • Microglia / drug effects*
  • Microglia / metabolism
  • Neuronal Plasticity
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Phosphatidylserines / metabolism
  • Phosphatidylserines / pharmacology*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Synapses / drug effects*
  • Synapses / genetics
  • Synapses / metabolism
  • Synaptic Transmission
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Vesicular Glutamate Transport Protein 2

Substances

  • GPR56 protein, mouse
  • Luminescent Proteins
  • Membrane Proteins
  • Phosphatidylserines
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled
  • Slc17a6 protein, mouse
  • TMEM30a protein, mouse
  • Vesicular Glutamate Transport Protein 2
  • red fluorescent protein