AP-4-mediated axonal transport controls endocannabinoid production in neurons

Nat Commun. 2022 Feb 25;13(1):1058. doi: 10.1038/s41467-022-28609-w.


The adaptor protein complex AP-4 mediates anterograde axonal transport and is essential for axon health. AP-4-deficient patients suffer from a severe neurodevelopmental and neurodegenerative disorder. Here we identify DAGLB (diacylglycerol lipase-beta), a key enzyme for generation of the endocannabinoid 2-AG (2-arachidonoylglycerol), as a cargo of AP-4 vesicles. During normal development, DAGLB is targeted to the axon, where 2-AG signalling drives axonal growth. We show that DAGLB accumulates at the trans-Golgi network of AP-4-deficient cells, that axonal DAGLB levels are reduced in neurons from a patient with AP-4 deficiency, and that 2-AG levels are reduced in the brains of AP-4 knockout mice. Importantly, we demonstrate that neurite growth defects of AP-4-deficient neurons are rescued by inhibition of MGLL (monoacylglycerol lipase), the enzyme responsible for 2-AG hydrolysis. Our study supports a new model for AP-4 deficiency syndrome in which axon growth defects arise through spatial dysregulation of endocannabinoid signalling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 4* / metabolism
  • Animals
  • Axonal Transport
  • Axons / metabolism
  • Endocannabinoids* / metabolism
  • Humans
  • Mice
  • Monoacylglycerol Lipases / genetics
  • Monoacylglycerol Lipases / metabolism
  • Neurons* / metabolism


  • Adaptor Protein Complex 4
  • Endocannabinoids
  • Monoacylglycerol Lipases