2. Academic Validation
  3. AP-4-mediated axonal transport controls endocannabinoid production in neurons

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.
Alexandra K Davies 1,  Julian E Alecu 2,  Marvin Ziegler 2 3,  Catherine G Vasilopoulou 4,  Fabrizio Merciai 4 5,  Hellen Jumo 2,  Wardiya Afshar-Saber 2,  Mustafa Sahin 2 6,  Darius Ebrahimi-Fakhari 2,  Georg H H Borner 7
Affiliations

Affiliations

  • 1 Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany. davies@biochem.mpg.de.
  • 2 Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
  • 3 Department of Functional Neuroanatomy, Institute of Anatomy and Cell Biology, Heidelberg University, INF 307, Heidelberg, 69120, Germany.
  • 4 Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany.
  • 5 Department of Pharmacy and PhD Program in Drug Discovery and Development, University of Salerno, 84084, Fisciano, SA, Italy.
  • 6 Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
  • 7 Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany. borner@biochem.mpg.de.
PMID: 35217685 DOI: 10.1038/s41467-022-28609-w
Abstract

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.

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