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AP-4 mediates vesicular transport of the 2-AG endocannabinoid producing enzyme DAGLB
bioRxiv - Cell Biology Pub Date : 2020-10-25 , DOI: 10.1101/2020.10.25.353995
Alexandra K. Davies , Marvin Ziegler , Hellen Jumo , Wardiya Afshar Saber , Darius Ebrahimi-Fakhari , Georg H. H. Borner

The adaptor protein complex AP-4 mediates anterograde axonal transport and is essential for axon health. AP-4-deficient patients suffer from a severe neurological disorder, which encompasses neurodevelopmental and neurodegenerative features. While impaired autophagy has been suggested to account for axon degeneration in AP-4 deficiency, axon growth defects occur through an unknown mechanism. Here we use orthogonal proteomic and imaging methods to identify DAGLB (diacylglycerol lipase-beta) as a cargo of AP-4 vesicles. DAGLB is a key enzyme for the generation of 2-AG (2-arachidonoylglycerol), the most abundant endocannabinoid in brain. During normal development, DAGLB is targeted to the axon, where 2-AG signalling drives axonal growth. We show that DAGLB accumulates at the TGN of AP-4-deficient cells, including in iPSC-derived neurons from a patient with AP-4 deficiency syndrome. Our data thus support that AP-4 mediates axonal targeting of DAGLB, and we propose that axon growth defects in AP-4 deficiency may arise through spatial dysregulation of endocannabinoid signalling.

中文翻译:

AP-4介导2-AG内源性大麻素产生酶DAGLB的囊泡转运

衔接蛋白复合物AP-4介导顺行轴突运输,是轴突健康必不可少的。缺乏AP-4的患者患有严重的神经系统疾病,其中包括神经发育和神经退行性病变。虽然自噬受损已被认为是AP-4缺乏引起轴突变性的原因,但轴突生长缺陷是通过未知的机制发生的。在这里,我们使用正交蛋白质组学和成像方法来识别DAGLB(二甘油甘油脂肪酶-β)作为AP-4囊泡的货物。DAGLB是产生2-AG(2-花生四烯酰甘油)(大脑中最丰富的内源性大麻素)的关键酶。在正常发育期间,DAGLB靶向轴突,其中2-AG信号传导驱动轴突生长。我们显示DAGLB累积在AP-4缺陷细胞的TGN处,包括来自患有AP-4缺乏症候群的患者的iPSC衍生神经元。因此,我们的数据支持AP-4介导DAGLB的轴突靶向作用,并且我们提出AP-4缺陷中的轴突生长缺陷可能是由于内源性大麻素信号传导的空间失调而引起的。
更新日期:2020-10-27
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