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

• Published in: Nature communications Vol. 13; no. 1; p. 1058
• Main Authors: Davies, Alexandra K, Alecu, Julian E, Ziegler, Marvin, Vasilopoulou, Catherine G, Merciai, Fabrizio, Jumo, Hellen, Afshar-Saber, Wardiya, Sahin, Mustafa, Ebrahimi-Fakhari, Darius, Borner, Georg H H
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 25.02.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: 2-Arachidonoylglycerol; Adaptor Protein Complex 4 - metabolism; Adaptor proteins; Animals; Axon guidance; Axonal Transport; Axons - metabolism; Children; Defects; Diglycerides; Endocannabinoids - metabolism; Enzymes; Golgi cells; Humans; Lipase; Lipoprotein lipase; Mice; Monoacylglycerol Lipases - genetics; Monoacylglycerol Lipases - metabolism; Neurodegenerative diseases; Neurodevelopmental disorders; Neurological diseases; Neurons; Neurons - metabolism; Signaling
• ISSN: 2041-1723; 2041-1723
• 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.