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University of Groningen Tryptophan metabolism in aging and disease Michels, Helen IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2017 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Michels, H. (2017). Tryptophan metabolism in aging and disease: Insights from Caenorhabditis elegans. [Groningen]: University of Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 12-11-2019 Tryptophan metabolism in aging and disease Insights from Caenorhabditis elegans PhD thesis by Helen Michels 513375-L-bw-michels Processed on: 29-8-2017 PDF page: 1 ISBN: 978-94-028-0754-7 Copyright: Helen Michels 2017 Comic design: Sebastian Busch Layout: Midas Mentink, PersoonlijkProefschrift.nl Printing: Ipskamp Drukkers, Enschede, the Netherlands 513375-L-bw-michels Processed on: 29-8-2017 PDF page: 2 Tryptophan metabolism in aging and disease Insights from Caenorhabditis elegans PhD thesis to obtain the degree of PhD at the University of Groningen on the authority of the Rector Magnificus Prof. E. Sterken and in accordance with the decision by the College of Deans. This thesis will be defended in public on Wednesday, 27 September 2017 at 12:45 by Helen Michels born on 30 June 1985 in Münster, Germany 513375-L-bw-michels Processed on: 29-8-2017 PDF page: 3 Supervisors Prof. E.A.A. Nollen Prof. I.P. Kema Assessment Committee Prof. R.P.H. Bischoff Prof. B.M. Bakker Prof. R. Korswagen 513375-L-bw-michels Processed on: 29-8-2017 PDF page: 4 513375-L-bw-michels Processed on: 29-8-2017 PDF page: 5 513375-L-bw-michels Processed on: 29-8-2017 PDF page: 6 TABLE OF CONTENTS Overview Outline of this thesis 10 Chapter I: Introduction 14 Chapter II: Genetic screens in Caenorhabditis elegans models for 56 neurodegenerative diseases Chapter III: Identification of an evolutionary conserved structural loop 82 that is required for the enzymatic and biological function of tryptophan 2,3-dioxygenase Chapter IV: Tryptophan 2,3-dioxygenase regulates health- and lifespan 100 independently of kynurenine, serotonin and tryptamine signaling in C. elegans Chapter V: Tryptophan 2,3-dioxygenase regulates motility and lifespan 118 independently of protein translation in C. elegans Chapter VI: Transcriptome profiling inC. elegans reveals that TDO and 132 other amino acid dioxygenases regulate mitochondrial capacity and healthspan Chapter VII: A screening-based platform for the assessment of cellular 164 respiration in Caenorhabditis elegans Chapter VIII: Increase in number and complexity of modified tryptophan 206 residues during aging in C. elegans Chapter IX: Discussion and perspectives 222 Summary 244 Samenvatting 248 List of publications 252 Appendix 256 Aknowledgement 266 513375-L-bw-michels Processed on: 29-8-2017 PDF page: 7 513375-L-bw-michels Processed on: 29-8-2017 PDF page: 8 Overview Outline of this thesis 513375-L-bw-michels Processed on: 29-8-2017 PDF page: 9 Chapter I starts by introducing the different hallmarks of aging. It describes how they might contribute to the aging process and the pathology of age-related diseases. The chapter focuses especially on the theories of aging that are based on loss in proteostasis, mitochondrial dysfunction and ROS production, and changes in nutrient sensing and processing. The chapter continues with the impact of amino acids on cellular metabolism emphasizing findings on the tryptophan 2,3-dioxygenases (TDO, TDO-2 in C. elegans), tryptophan metabolism and its metabolites. Finally, it lists open questions on the mechanisms by which depletion of tdo-2 leads to a health- and lifespan extension that led to the aim of this study. Chapter II explains the power of using C. elegans for high-throughput screens in order to discover routes that have implications in neurodegenerative diseases. It compares the two most frequently used screening methods - EMS mutagenesis and RNA interference – by describing the advantages and disadvantages for each method. We finish by summarizing findings in the field of neurodegeneration that are based on genetic screens in C. elegans models for Parkinson’s, Alzheimer’s and polyglutamine diseases. Chapter III gives insight in the molecule structure of TDO-2 by comparing different C. elegans deletion mutants that were generated by the CRISPR/Cas9 system. It shows that 3 amino acids situated in the loop between two alpha- helices, predicted to bind haem, are essential for the enzyme function. Tryptophan is a precursor for a range of metabolites including serotonin, tryptamine and the downstream products of the kynurenine pathway called kynurenines. Chapter IV investigates the possibility that an increase in the amount of free tryptophan and changes in the metabolite levels might be responsible for the health- and lifespan increasing effects of tdo-2 depletion. The results indicate that the two phenotypes are independent of tryptophan metabolites. Tryptophan is the least abundant essential amino acid. Chapter V deals with the possibility that an increase in free tryptophan levels might influence translational rates within the cell and that this might be the underlying mechanism for the health- and lifespan benefits intdo-2 depleted animals. The results show that the function of TDO-2 in regulating health- and lifespan in C. elegans is independent of changes in cytosolic and mitochondrial translation. Chapter VI further explores the cellular and transcriptomic changes in tdo-2 depleted animals and reveals that TDO-2 is involved in the regulation of mitochondrial activity. It further finds that two other dioxygenases, HPD-1 and CDO-1, are sharing the same phenotypes when depleted and that the regulation of the mitochondrial respiration 10 513375-L-bw-michels Processed on: 29-8-2017 PDF page: 10 might be via similar mechanisms. It suggests that this is only true for enzymes that combine the dioxygenase activity with amino acid degradation and therefore O proposes a general role of amino acid dioxygenases in control of mitochondrial activity, health- and lifespan in C. elegans. Chapter VII presents the establishment of a protocol to measure C. elegans’ respiration with the help of the Seahorse XF cycler that was initially constructed for cell-based assays. It shows optimizations of every single step including the use of different drugs. The chapter gives a guideline how to implement this method to answer whether a treatment or genetic modification might influence general but also mitochondrial specific respiration. Chapter VIII switches the focus from free tryptophan to single tryptophan residues within proteins. Preliminary results show that the amount and variety of modification on tryptophan residues in a polypeptide increases with age. It suggests a range of assays to test whether and how depletion of tdo-2 might change the number and composition of these modifications and whether this might have implication on the aging process. Chapter IX summarizes the findings of this thesis and discusses the open question and next steps of research on how TDO-2 influences cellular processes especially on the level of mitochondria to improve the animals’ fitness and to extend its lifespan. It describes the resemblance of amino acid dioxygenases and a possible new view on aging. It concentrates on the possibilities how the findings might help to understand the molecular basis of aging and age-related diseases. 11 513375-L-bw-michels Processed on: 29-8-2017 PDF page: 11 513375-L-bw-michels Processed on: 29-8-2017 PDF page: 12 Chapter I Introduction Helen Michels1 1European Research Institute for the Biology of Aging, University of Groningen, University Medical Centre Groningen, Laboratory of Molecular Neurobiology of Aging, The Netherlands 513375-L-bw-michels Processed on: 29-8-2017 PDF page: 13 The increasing age of the world’s population is accompanied by increasing numbers of individuals suffering from age-related pathologies such as neurodegenerative diseases, cancer and type 2 diabetes. This development demands increasing efforts from society, either financially or in terms of more specialized or prolonged care for the elderly. In turn, this raises questions such as how do age-related diseases develop? How do we age in general? And how can we modulate age-related processes to prolong the lifespan in such a health-promoting way that it is worth living longer and that less care is needed? This chapter summarizes the findings of aging research over the past decades by dividing them into nine different hallmarks of aging. It also emphasizes findings on the three hallmarks that are relevant to this thesis: age-related loss of proteostasis, dysfunction of mitochondria, and changes in nutrient sensing and processing. The chapter then continues by describing the effects of amino acids on the aging process. It focuses on tryptophan, an essential amino acid that controls translational rates and is a precursor for bioactive amines that are involved in intracellular signaling and neurotransmission. These include serotonin and the downstream products of the kynurenine pathway such as the neuroactive molecules kynurenic acid, quinolinic acid and kynurenine. The end of the chapter focuses on one central enzyme of tryptophan metabolism: tryptophan 2,3-dioxygenase (TDO in humans, TDO-2 in the nematode Caenorhabditis elegans).
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