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
  • 1. Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany. [email protected].
  • 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. [email protected].
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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