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Regulation of Expression and Cellular Release of Acetylcholinesterase

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Regulation of Expression and Cellular Release of Acetylcholinesterase Regulation of expression and cellular release of acetylcholinesterase David Hicks Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Molecular and Cellular Biology Faculty of Biological Sciences August 2013 The candidate confirms that the work submitted is his own, except where work which has formed part of jointly authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly indicated below. The candidate confirms that appropriate credit has been given within the thesis where reference has been made to the work of others. Chapters 3 and 4 are based on work from jointly authored publications, namely Hicks, D. A., Makova, N. Z., Nalivaeva, N. N. & Turner, A. J. 2013. Characterisation of acetylcholinesterase release from neuronal cells. Chem Biol Interact, 203, 302-308 and Hicks DA, Makova NZ, Gough M, Parkin ET, Nalivaeva NN, Turner AJ (2013) The amyloid precursor protein represses transcription of acetylcholinesterase in neuronal cell lines. J Biol Chem. Accepted. All of the data in these papers that are present in this thesis are attributable to me. The contribution of other authors was in the form of preliminary work (N. Z. Makova), DNA constructs (M. Gough, E. T. Parkin) or editorial work (N. N. Nalivaeva and A. J. Turner). This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. © 2013 The University of Leeds and David Hicks The right of David Hicks to be identified as author of this work has been asserted by him in accordance with the Copyright, Designs and Patents Act 1988. Acknowledgements Firstly, I would like to thank Prof. Tony Turner and Dr. Natasha Nalivaeva for, in short, my doctorate. Without the opportunity afforded to me and their constant support, this thesis would never have been written. During this project, spanning four years, they have always been encouraging, patient and helpful, offering direction and insight throughout. Tony and Natasha have been incredibly proactive in encouraging me to publish in peer-reviewed journals and attend a range of conferences, both of which have been of incalculable benefit. I would also like to thank all the members of the Turner lab who contributed to such a convivial, collaborative and productive environment during my time here, namely Drs Nikolai Belyaev, Nicky Clarke, Caroline Kerridge and Ali Whyteside. I reserve special acknowledgement for Natasha Makova and Paul Kelly, whose general efficiency and excellence is much appreciated. Members of other labs at the University of Leeds have been of great help to me. I thank those with whom I did my three month rotations, Drs Zaineb Henderson and Danielle John and also Drs Hugh Pearson and Rakesh Suman. I am also extremely grateful to Prof. Nigel Hooper who, as my assessor, has provided many helpful comments on the progress of this work. I have benefited significantly from the generosity within the scientific community, receiving DNA constructs and cells from researchers across the world. They include Prof. S. Johansson, Uppsala University, Sweden; Prof. C. Pietrzik and Dr. S. Isbert, Johannes Gutenberg University Mainz, Germany; Prof. K. Tsim, Hong Kong University of Science and Technology, Hong Kong; Dr. E. Parkin and M. Gough, Lancaster University; and from the University of Leeds, Drs I. Wood and I. Whitehouse. Finally, I would like to thank the BBSRC for funding my research. As I go on to write a new chapter in my scientific career, I would like to reiterate my enormous gratitude to everyone listed here for their contributions to the five chapters herein. i Publications Hicks DA, Makova NZ, Gough M, Parkin ET, Nalivaeva NN, Turner AJ (2013) The amyloid precursor protein represses transcription of acetylcholinesterase in neuronal cell lines. J Biol Chem. 286, 26039-26051 Hicks DA, Makova NZ, Nalivaeva NN, Turner AJ (2013) Characterisation of acetylcholinesterase release from neuronal cells. Chem Biol Interact. 203, 302-308 Neelov IM, Klajnert B, Makova NZ, Hicks D, Pearson H, Vlasov GP, Ilyash MY, Vasilev DS, Dubrovskaya NM, Tumanova NL, Zhuravin IA, Turner AJ, Nalivaeva NN (2012) Molecular properties of lysine dendrimers and their interactions with Aβ peptides and neuronal cells. Curr Med Chem. 20,134-143 Hicks DA, Nalivaeva NN, Turner AJ. (2012) Lipid rafts and Alzheimer's disease: protein-lipid interactions and perturbation of signaling. Front Physiol. 3,189 Hicks D, John D, Makova NZ, Henderson Z, Nalivaeva NN, Turner AJ (2011) Membrane targeting, shedding and protein interactions of brain acetylcholinesterase. J Neurochem. 116,742-746 ii Abstract Acetylcholinesterase (AChE) is a hydrolytic enzyme which has been linked to the pathological progression of the neurodegenerative disease, Alzheimer’s disease (AD). AD is thought to be driven by the toxic amyloid-β (Aβ) peptide, which derives from proteolytic cleavage of amyloid precursor protein (APP). Here, release of AChE from two neuronal cell lines, SN56 and SH-SY5Y, was investigated and found to be driven by at least two distinct pathways, shedding and exocytosis. The former was found to be mediated by an unknown metalloprotease, sensitive to the inhibitor batimastat. Shedding was also found to be dependent on the action of protein disulphide isomerase. The cellular release of AChE was potentiated by agonism of muscarinic acetylcholine receptors (mAChRs) by carbachol. This process was found to derive, in part, from transcriptional upregulation of AChE by mAChRs, likely involving the Egr-1 transcription factor. Subsequent work established, for the first time, a mechanistic link between APP and regulation of AChE expression. Over-expression of APP in neuronal cell lines led to reductions of AChE mRNA, protein and catalytic activity. Assessment of other cholinergic genes revealed repression, by APP, of the membrane anchor of AChE, PRiMA, but no changes in mRNA levels of butyrylcholinesterase or the high affinity choline transporter, CHT. This regulatory relationship between APP and AChE was confirmed when knockdown of APP in wild type SN56 cells resulted in a significant increase in AChE mRNA. The ability of APP to repress AChE transcription was shown to be independent of proteolytic processing of the former, as inhibition of each of the secretase enzymes responsible for APP proteolysis had no effect on AChE activity. However, APP-mediated repression of AChE was dependent on the N-terminal, extracellular E1 domain and specifically the copper-binding domain within. Deletion of these domains completely ablated the ability of APP to effect transcriptional repression of AChE. These studies have implications for greater understanding of the role of the cholinergic system and AChE in the pathological progression of AD. This work further elucidates a physiological role for APP, the perturbation of which may contribute to neurodegeneration. iii Contents Acknowledgements ............................................................................................................ i Publications ....................................................................................................................... ii Abstract ............................................................................................................................ iii Table of Figures ............................................................................................................... xi Abbreviations ................................................................................................................. xiii Chapter 1: Introduction ..................................................................................................... 1 1.1 The cholinergic system ............................................................................................... 1 1.1.1 Brain regions and development ............................................................................ 1 1.1.2 Function ............................................................................................................... 2 1.1.3 Choline acetyltransferase and the cholinergic synapse ........................................ 4 1.1.4 The nicotinic acetylcholine receptors (nAChRs) ............................................ 6 1.1.4.1 The α7 nAChR ........................................................................................ 8 1.1.5 The muscarinic acetylcholine receptors (mAChRs) ....................................... 9 1.1.5.1 The M1 mAChR .......................................................................................... 10 1.1.5.2 Gene regulation ........................................................................................... 10 1.1.5.2.1 Egr family proteins ................................................................................... 11 ................................................................................................................................. 12 1.1.5.2.3 Elk-1 as a regulatory TF ........................................................................... 13 1.1.6 Trophic factors and receptors ....................................................................... 13 1.1.6.1 Nerve growth factor (NGF) ................................................................... 14 1.1.6.2 p75 pan-neurotrophin receptor (p75NTR) ..................................................... 14 1.2 The cholinesterases .............................................................................................
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