Reduced levels of a key enzyme affect neurite growth
The study identified reduced levels of a key enzyme both in neurons from a person with AP-4 deficiency and in the brains of AP-4 mice. Through a cascade of events, the end result is neurite growth defects in the axon.
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 signaling 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 signaling.
SOURCE: Nat Commun. 2022 Feb 25;13(1):1058. doi: 10.1038/s41467-022-28609-w. PMID: 35217685 © 2022. The Author(s).
AP-4-mediated axonal transport controls endocannabinoid production in neurons
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
1. Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany.
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.