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

Alexandra K. Davies (), Julian E. Alecu, Marvin Ziegler, Catherine G. Vasilopoulou, Fabrizio Merciai, Hellen Jumo, Wardiya Afshar-Saber, Mustafa Sahin, Darius Ebrahimi-Fakhari and Georg H. H. Borner ()
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Alexandra K. Davies: Max Planck Institute of Biochemistry
Julian E. Alecu: Harvard Medical School
Marvin Ziegler: Harvard Medical School
Catherine G. Vasilopoulou: Max Planck Institute of Biochemistry
Fabrizio Merciai: Max Planck Institute of Biochemistry
Hellen Jumo: Harvard Medical School
Wardiya Afshar-Saber: Harvard Medical School
Mustafa Sahin: Harvard Medical School
Darius Ebrahimi-Fakhari: Harvard Medical School
Georg H. H. Borner: Max Planck Institute of Biochemistry

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28609-w

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