Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3

Martina Pigoni; Hung-En Hsia; Jana Hartmann; Jasenka Rudan Njavro; Merav D Shmueli; Stephan A Mueller; Gokhan Guener; Johanna Tueshaus; Peer-Hendrik Kuhn; Rohit Kumar; Pan Gao; Mai Ly Tran; Bulat Ramazanov; Birgit Blank; Agnes L Hipgrave Ederveen; Julia Von Blume; Christophe Mulle; Jenny M Gunnersen; Manfred Wuhrer; Gerhard Rammes; Marc Aurel Busche; Thomas Koeglsperger; Stefan F Lichtenthaler

Journal article

Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3

Martina Pigoni, Hung-En Hsia, Jana Hartmann, Jasenka Rudan Njavro, Merav D Shmueli, Stephan A Mueller, Gokhan Guener, Johanna Tueshaus, Peer-Hendrik Kuhn, Rohit Kumar, Pan Gao, Mai Ly Tran, Bulat Ramazanov, Birgit Blank, Agnes L Hipgrave Ederveen, Julia Von Blume, Christophe Mulle, Jenny M Gunnersen, Manfred Wuhrer, Gerhard Rammes Show all

EMBO JOURNAL | WILEY | Published : 2020

DOI: 10.15252/embj.2019103457

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Abstract

Seizure protein 6 (SEZ6) is required for the development and maintenance of the nervous system, is a major substrate of the protease BACE1 and is linked to Alzheimer's disease (AD) and psychiatric disorders, but its molecular functions are not well understood. Here, we demonstrate that SEZ6 controls glycosylation and cell surface localization of kainate receptors composed of GluK2/3 subunits. Loss of SEZ6 reduced surface levels of GluK2/3 in primary neurons and reduced kainate-evoked currents in CA1 pyramidal neurons in acute hippocampal slices. Mechanistically, loss of SEZ6 in vitro and in vivo prevented modification of GluK2/3 with the human natural killer-1 (HNK-1) glycan, a modulator of ..

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University of Melbourne Researchers

Jenny Gunnersen Author Anatomy and Physiology

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Awarded by Deutsche Forschungsgemeinschaft (German Research Foundation)

Awarded by Alzheimer Research UK

Awarded by UKRI Future Leaders Fellowship

Awarded by BrightFocus Foundation

Awarded by National Institute of General Medical Sciences of the United States National Institutes of Health

Awarded by Australian National Health and Medical Research Council

Funding Acknowledgements

We thank Katrin Moschke, Anna Berghofer, Claudia Ihbe, and Marek-Jan Czyz for their technical assistance. We thank Hiroshi Takeshima for providing triple SEZ6 KO mice. This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy-ID 390857198) and the research unit FOR2290, by the Centers of Excellence in Neurodegeneration, the BMBF through grant CLINSPECT-M, the JPND project PMG-AD, and the Bayerisches Hochschulzentrum fur Mittel-, Ost- und Sudosteuropa (BAYHOST). M.A.B. and J.H. are supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the Medical Research Council, Alzheimer's Society and Alzheimer Research UK (UKDRI-1010). M.A.B. is also funded by a UKRI Future Leaders Fellowship (MR/S017003/1) and a grant from the BrightFocus Foundation (A2019112S). J.v.B was funded by the National Institute of General Medical Sciences of the United States National Institutes of Health, award number GM134083-01. J.M.G. is funded by the Australian National Health and Medical Research Council (GNT10008046, GNT1058672, GNT1140050). TK has been supported by Parkinson Fonds Deutschland, Hilde Ulrichs Stiftung, Friede Springer Stiftung, Deutsche Stiftung fur Neurologie, Luneburg Heritage.