School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, Division of Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
Department of Human Physiology, Centre for Neuroscience, Flinders University, Adelaide, SA, 5000, Australia.
Mol Neurobiol. 2018 Mar;55(3):1815-1830. doi: 10.1007/s12035-016-0379-0. Epub 2017 Jan 12.
When BDNF binds to its receptors, TrkB and p75, the BDNF-receptor complex is endocytosed and trafficked to the cell body for downstream signal transduction, which plays a critical role in neuronal functions. Huntingtin-associated protein 1 (HAP1) is involved in trafficking of vesicles intracellularly and also interacts with several membrane proteins including TrkB. Although it has been known that HAP1 has functions in vesicular trafficking and receptor stabilisation, it is not yet established whether HAP1 has a role in BDNF and its receptor endocytosis. In the present study, we found that HAP1 is in an interacting complex with p75, TrkB and BDNF, especially newly endocytosed BDNF. BDNF and TrkB internalisation is abolished in HAP1 knock-out (KO) cortical neurons. TrkB downstream signalling pathways such as ERK, Akt and PLCγ-1 are also impaired in HAP1 KO cortical neurons upon BDNF stimulation. Proliferation of cerebellar granule cells is also impaired in cell culture and cerebellum of HAP1 KO mice. Our findings suggest that HAP1 may play a key role in BDNF and its receptor endocytosis and may promote neuronal survival and proliferation.
当 BDNF 与其受体 TrkB 和 p75 结合时，BDNF-受体复合物被内吞并转运到细胞体进行下游信号转导，这在神经元功能中起着关键作用。Huntingtin 相关蛋白 1（HAP1）参与囊泡的细胞内运输，并且还与包括 TrkB 在内的几种膜蛋白相互作用。尽管已经知道 HAP1 在囊泡运输和受体稳定化方面具有功能，但尚未确定 HAP1 是否在 BDNF 及其受体内吞作用中发挥作用。在本研究中，我们发现 HAP1 与 p75、TrkB 和 BDNF 形成相互作用复合物，特别是新内吞的 BDNF。在 HAP1 敲除（KO）皮质神经元中，BDNF 和 TrkB 的内化被消除。BDNF 刺激后，HAP1 KO 皮质神经元中的 TrkB 下游信号通路，如 ERK、Akt 和 PLCγ-1 也受损。小脑颗粒细胞在细胞培养和 HAP1 KO 小鼠小脑中的增殖也受损。我们的研究结果表明，HAP1 可能在 BDNF 及其受体内吞作用中发挥关键作用，并可能促进神经元存活和增殖。
