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


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. © 2022. The Author(s).

Authors Davies AK, Alecu JE, Ziegler M, Vasilopoulou CG, Merciai F, Jumo H, Afshar-Saber W, Sahin M, Ebrahimi-Fakhari D, Borner GHH
Journal Nature communications
Publication Date 2022 Feb 25;13(1):1058
PubMed 35217685
PubMed Central PMC8881493
DOI 10.1038/s41467-022-28609-w

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