Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany.
Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Nat Commun. 2022 Feb 25;13(1):1058. doi: 10.1038/s41467-022-28609-w.
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.
衔接蛋白复合物 AP-4 介导顺行轴突运输，对轴突健康至关重要。AP-4 缺乏的患者患有严重的神经发育和神经退行性疾病。在这里，我们鉴定出二酰基甘油脂肪酶-β（DAGLB），一种生成内源性大麻素 2-AG（2-花生四烯酸甘油）的关键酶，是 AP-4 囊泡的货物。在正常发育过程中，DAGLB 被靶向到轴突，在那里 2-AG 信号驱动轴突生长。我们表明，DAGLB 在 AP-4 缺乏细胞的反式高尔基体网络中积累，AP-4 缺乏症患者的神经元中轴突 DAGLB 水平降低，AP-4 敲除小鼠的大脑中 2-AG 水平降低。重要的是，我们证明抑制 2-AG 水解的酶 MGLL（单酰基甘油脂肪酶）可挽救 AP-4 缺乏神经元的神经突生长缺陷。我们的研究支持 AP-4 缺乏综合征的新模型，其中轴突生长缺陷是通过内源性大麻素信号的空间失调引起的。
