Phosphatidylinositol 3,5-bisphosphate facilitates axonal vesicle transport and presynapse assembly

Science. 2023 Oct 13;382(6667):223-230. doi: 10.1126/science.adg1075. Epub 2023 Oct 12.

Abstract

Neurons relay information via specialized presynaptic compartments for neurotransmission. Unlike conventional organelles, the specialized apparatus characterizing the neuronal presynapse must form de novo. How the components for presynaptic neurotransmission are transported and assembled is poorly understood. Our results show that the rare late endosomal signaling lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] directs the axonal cotransport of synaptic vesicle and active zone proteins in precursor vesicles in human neurons. Precursor vesicles are distinct from conventional secretory organelles, endosomes, and degradative lysosomes and are transported by coincident detection of PI(3,5)P2 and active ARL8 via kinesin KIF1A to the presynaptic compartment. Our findings identify a crucial mechanism that mediates the delivery of synaptic vesicle and active zone proteins to developing synapses.

MeSH terms

  • Axonal Transport* / physiology
  • Humans
  • Kinesins / metabolism
  • Neurons* / metabolism
  • Phosphatidylinositol Phosphates* / metabolism
  • Synaptic Vesicles* / metabolism

Substances

  • KIF1A protein, human
  • Kinesins
  • phosphatidylinositol 3,5-diphosphate
  • Phosphatidylinositol Phosphates