HAP1 Is Required for Endocytosis and Signalling of BDNF and Its Receptors in Neurons

• Type of Material: Article
• Authors: Yoon Lim, University of South Australia; Linda Lin-Yan Wu, Flinders University South Australia; Si Chen, Flinders University South Australia; Ying Sun, University of South Australia; Swarna Lekha Vijayaraj, Flinders University South Australia; Miao Yang, University of South Australia; Larisa Bobrovskaya, University of South Australia; Damien Keating, Flinders University South Australia; Xiao-Jiang Li, Emory University; Xin-Fu Zhou, University of South Australia
• Language: English
• Date: 2018-03-01
• Publisher: Humana Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017, Springer Science+Business Media New York.
• Final Published Version (URL): http://dx.doi.org/10.1007/s12035-016-0379-0
• Title of Journal or Parent Work: Molecular Neurobiology
• ISSN: 0893-7648
• Volume: 55
• Issue: 3
• Start Page: 1815
• End Page: 1830
• Grant/Funding Information: This project was supported by an NHMRC grant to XFZ&XJL (480423).; Yoon Lim was supported by an NHMRC Postgraduate Scholarship (GNT1017711), and LLW was supported by an IPRS Scholarship from Flinders University.
• Keywords: INTERACTS; TRUNCATED TRKB RECEPTORS; BRAIN; HUNTINGTIN-ASSOCIATED PROTEIN-1; Endocytosis; Proliferation; GROWTH; CELL-SURVIVAL; INTRACELLULAR TRAFFICKING; Neurosciences; P75NTR; Science & Technology; TrkB; Neurosciences & Neurology; IN-VITRO; HAP1; Life Sciences & Biomedicine; BDNF; NEURITE OUTGROWTH; NEUROTROPHIC FACTOR
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

When BDNF binds to its receptors, TrkB and p75 NTR , 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 NTR , 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.