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

Tao Li; Diankun Yu; Hayeon C Oak; Beika Zhu; Li Wang; Xueqiao Jiang; Robert S Molday; Arnold Kriegstein; Xianhua Piao

doi:10.15252/embj.2021107915

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.

Authors

Tao Li^{1

2}, Diankun Yu^{1

2}, Hayeon C Oak^{1

2}, Beika Zhu^{1

2}, Li Wang^{1

3}, Xueqiao Jiang^{1

2}, Robert S Molday⁴, Arnold Kriegstein^{1

3}, Xianhua Piao^{1

2

5

6}

Affiliations

¹ Weill Institute for Neuroscience, University of California, San Francisco (UCSF), San Francisco, CA, USA.
² Newborn Brain Research Institute, University of California, San Francisco (UCSF), San Francisco, CA, USA.
³ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
⁵ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA.
⁶ Division of Neonatology, Department of Pediatrics, University of California, San Francisco (UCSF), San Francisco, CA, USA.

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
Red Fluorescent Protein
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

Abstract

Publication types

MeSH terms

Substances

Grants and funding