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

Davies, A. K., Alecu, J. E., Ziegler, M., Vasilopoulou, C. G., Merciai, F., Jumo, H., et al. (2022). AP-4-mediated axonal transport controls endocannabinoid production in neurons. Nature Communications, 13(1): 1058. doi:10.1038/s41467-022-28609-w.

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 Creators:
Davies, Alexandra K.1, Author              
Alecu, Julian E.2, Author
Ziegler, Marvin2, Author
Vasilopoulou, Catherine G.1, Author              
Merciai, Fabrizio1, Author
Jumo, Hellen2, Author
Afshar-Saber, Wardiya2, Author
Sahin, Mustafa2, Author
Ebrahimi-Fakhari, Darius2, Author
Borner, Georg H. H.3, Author              
Affiliations:
1Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              
2external, ou_persistent22              
3Borner, Georg / Systems Biology of Membrane Trafficking, Max Planck Institute of Biochemistry, Max Planck Society, ou_3060205              

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Free keywords: COMPLEX 4 DEFICIENCY; SPASTIC PARAPLEGIA; ACCESSORY PROTEIN; PROTEOMICS DATA; BRAIN; PLATFORM; GROWTH; SUPPRESSION; INDUCTION; AUTOPHAGYScience & Technology - Other Topics;
 Abstract: Davies et al. identify a putative mechanism underlying the childhood neurological disorder AP-4 deficiency syndrome. In the absence of AP-4, an enzyme that makes 2-AG is not transported to the axon, leading to axonal growth defects, which can be rescued by inhibition of 2-AG breakdown. 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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Language(s): eng - English
 Dates: 2022
 Publication Status: Published online
 Pages: 17
 Publishing info: -
 Table of Contents: Special thanks to the MPIB Imaging Facility for outstanding technical support, in particular to Giovanni Cardone for his advice and assistance with the implementation of image analysis pipelines, as well as feedback on the manuscript, and to Martin Spitaler for his expert technical advice for imaging experiments.
 Rev. Type: -
 Degree: -

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Project name : Marie Sklodowska-Curie grant agreement
Grant ID : 896725
Funding program : Horizon 2020 (H2020)
Funding organization : European Commission (EC)

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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 13 (1) Sequence Number: 1058 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723