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

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.

The Relationship between the Aberrant Long Non-Coding RNA-Mediated Competitive Endogenous RNA Network and Alzheimer’s Disease Pathogenesis

“…Regarding the upregulated lncRNA-associated ceRNA network, MSTRG.6775.12 had the highest FoldChange value in the hippocampus and possible ceRNA actions with 16 miRNAs, thus regulating the expression of 19 downstream mRNAs. Furthermore, ENSMUST00000150127 showed a potential regulatory relationship with miR-3064-5p and miR-3085-3p, resulting in the altered expression of several mRNAs, such as Wdfy1 [ 21 ], Mgll [ 22 ], and Cntn2 [ 23 ], related to neurodevelopmental functions and neurodegenerative mechanisms. In the downregulated lncRNA-associated ceRNA network, MSTRG.17585.1 potentially targeted several miRNAs, among which miR-3065-5p has been shown to be specifically expressed in the plasma of AD patients, differentiating AD from other cognitive disorders [ 24 ].…”

The adaptor protein chaperone AAGAB stabilizes AP-4 complex subunits

“…, 2020 ; Behne et al. , 2020 ) and endocannabinoid signaling ( Davies et al. , 2022 ), respectively—both processes that are important for normal skin physiology ( Klapan et al.…”

“…, 2020 ), SERINC1 and SERINC3 ( Davies et al. , 2018 ), and DAGLB ( Davies et al. , 2022 ), from the TGN toward the cell periphery.…”

Deep and fast label-free Dynamic Organellar Mapping

“…Dynamic organellar maps (DOMs) capture protein localizations and their changes at the proteomic scale, and the approach has driven diverse discoveries in cell and medical biology [11,[13][14][15][16][17]. The bottleneck of our original DDA-based workflow was the considerable MS time required to achieve deep coverage.…”

“…Since DOMs are highly reproducible, they allow capture of induced protein localization changes, and have thus driven phenotype discovery in diverse biological contexts. For example, DOMs have been applied to reveal the molecular pathomechanisms of AP-4 deficiency syndrome, a severe neurological disorder [13,14]; to characterize the function of a lysosomal retrieval pathway [15]; to quantify translocation events triggered during EGF signalling [11]; to identify the target of drugs selected from a phenotypic screen [16]; and to uncover how HIV infection alters the composition of extracellular vesicles [17].…”