title: HAP1 Is Required for Endocytosis and Signalling of BDNF and Its Receptors in Neurons.
abstract: When BDNF binds to its receptors, TrkB and p75NTR, 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 p75NTR, 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.
authors.affiliation: 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.
authors.forename: Yoon
authors.identifier: http://orcid.org/0000-0003-1110-1969
authors.initials: Y
authors.lastname: Lim
authors.affiliation: Department of Human Physiology, Centre for Neuroscience, Flinders University, Adelaide, SA, 5000, Australia.
authors.forename: Linda Lin-Yan
authors.initials: LL
authors.lastname: Wu
authors.affiliation: Department of Human Physiology, Centre for Neuroscience, Flinders University, Adelaide, SA, 5000, Australia.
authors.forename: Si
authors.initials: S
authors.lastname: Chen
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, Division of Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Human Physiology, Centre for Neuroscience, Flinders University, Adelaide, SA, 5000, Australia.
authors.forename: Swarna Lekha
authors.initials: SL
authors.lastname: Vijayaraj
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, Division of Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
authors.forename: Miao
authors.initials: M
authors.lastname: Yang
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, Division of Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
authors.forename: Larisa
authors.initials: L
authors.lastname: Bobrovskaya
authors.affiliation: Department of Human Physiology, Centre for Neuroscience, Flinders University, Adelaide, SA, 5000, Australia.
authors.forename: Damien
authors.initials: D
authors.lastname: Keating
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, Division of Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia. xin-fu.zhou@unisa.edu.au.
authors.forename: Xin-Fu
authors.initials: XF
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C490758:Hap1 protein, mouse; D009419:Nerve Tissue Proteins; D020813:Receptor, trkB
keywords: BDNF; Endocytosis; HAP1; P75NTR; Proliferation; TrkB