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Molecular Insights Into Amyloid Toxicity Using Model Lipid Membranes

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Molecular Insights Into Amyloid Toxicity Using Model Lipid Membranes Molecular insights into Amyloid toxicity using model lipid membranes A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Varun Prasath Babu Reddiar BSc (Biotechnology) Monash University & MSc (Biotechnology) Deakin University School of Science College of Science, Engineering and Health RMIT University March 2019 Declaration I certify that except where due to acknowledgement has been made, the work is that of the author alone; the work has not been submitted previously, in whole or in part, to qualify for any other academic award; the content of the thesis is the result of work which has been carried out since the official commencement date of the approved research program; any editorial work, paid or unpaid, carried out by a third party is acknowledged; and, ethics procedures and guidelines have been followed. I acknowledge the support I have received for my research through the provision of an RMIT Research Stipend Scholarship. B. Varun Prasath 1st March 2019 II Acknowledgements This thesis covers the research I have conducted during the last four years during my PhD education in Chemistry at RMIT University, in Melbourne, Australia. The location on which this research conducted and thesis written was traditionally owned by the Wurundjeri people of the Kulin nation, and I respect the elder’s past, present and emerging. I want to take this opportunity to mention a few people who have assisted and supported me to achieve this milestone. Drummond Supervisory Team and collaborators This PhD program was fully funded through Higher Degree by Research professional scholarship and along with a stipend for the duration of my PhD program. This research project was supervised by both Professor Calum J Drummond who is also the Deputy Vice-Chancellor of Research and Innovation and Associate Professor Charlotte E Conn from the first day to submission. I want to thank both my supervisors, for their patience, guidance, encouragement and advice they have provided throughout my time as their student. Charlotte and Calum were critical to keeping me on task and maintaining direction for this project through regular meetings which were important and invaluable for me. I have been extremely lucky to have them as my supervisors, who cared so much and above all I appreciate their humility and honesty, which allowed me to grow and develop myself over the years. I honestly have no words to describe my appreciation for Charlotte. She is a very caring person, also extremely passionate about research which is reflected by her accomplishments which are remarkable. Her undivided attention and support got me this far in my PhD, and she is an ideal role model for me. I would like to thank Dr. Nicholas (Nick) Reynolds at Swinburne University, Melbourne and Dr. Celine Valery at RMIT (Bundoora campus) and Associate Professor Helmut Hugel at RMIT (City Campus), for their supervision and support. Especially, Nick for imaging the samples I had prepared, and I am indebted for his contribution. Also, I would like to thank SAXS/WAXS beamline scientists (Dr Stephen Mudie and Dr Nigel Kirby) for their assistance with SAXS experiments at the Australian Synchrotron. Also, I’d like to thank Karin Vittrup, Soren Pape Moller and Nykola (Nyk) Jones at ISA, Centre for III Storage Ring Facilities in Aarhus (Denmark), especially, Nyk for assisting me with SRCD experiments. I would like to thank my colleagues mainly, Asoka Weerawardena, Dr. Maggie Zhai, Dr. Thomas Meikle, Dr. Brendan Dyett, Dr. Leonie Van ’t Hag, Jamie Strachan, Radhika Arunkumar, Dilek Yalcin Tuncali, Hayden Broomhall and Sachini Kadaoluwa, who have assisted me with my project during my supervisor’s absence. The Technical staff were also critical to the completion of this project, therefore, thank you, Shane Edmonds, Rebecca Flower, Erica McDonald, Dilara Kaymakci, Tanya Nguyen-Milgate, Karl Lang, Bebeto Lay, Vivian Basile, Ruth Cepriano-Hall, Howard Anderson and Fiona De-Mendonca. A huge thanks to all the admins and security personnel’s at RMIT, for creating such a dynamic, fun and above all, a safe environment for all of us. I have experienced a tonne of support, culture and extracurricular activities that made my four years a lot more bearable. Family and close friends Lastly, though certainly not least, to my close friends in research and outside academia, provided a much-needed form of escape from my studies, also deserve thanks for helping me keep things in perspective. Completing this work would have been all the more difficult were it not for the support and friendship of Dr. Andrew Coley, Dr. William Sullivan, Julia Liang, Dr. Mandeep Singh, Durga Dharmadana, Dr. Thomas McGrath, Timothy Coggan, Damien Moodie, Patience Shoko, Dr. Firoozeh Pourjavahe, Sana Subzwari, Buddima Edi, Sutha Satgunarajah, Buraq Tirli and Stuart Brown, thank you all very much. To my very close family, I must express my gratitude to my beautiful wife Veena Vibhushini, for her continued support and encouragement. I was continually amazed by her willingness to proofread countless pages of my thesis and listen to several mock presentations. Also, thanks to the unconditional love and support received from my parents (Thilaga Rani and Babu Reddiar) and in-laws (Maheshwari and Balakrishnan). I would like to thank my sisters, Sanjeevini and Gayathiri along with my brother in law Sooriya and niece Shanaya for their love, support and encouragement. Lastly, my adorable pets, Tony and Cooper for keeping me active and healthy and above all they have helped me get through the tough times. IV Conference presentations Experimental work from chapter 3, the effects of lipid composition on fibrillisation of the functional amyloid-forming peptide Somatostatin-14, was presented at two conferences where the details are listed below. 1. Australian Colloid and Surface science student conference, February 16 – 18, 2016, Sydney, Australia 2. Enabling Capability Platform conference, February 11 – 13, 2017, Melbourne, Australia V Abstract Functional amyloid-forming peptides can be found in nature, including stored in secretory granules as hormones. In contrast to toxic amyloid-forming peptides, the fibrillisation process for functional amyloids is typically “reversible”, a mechanism that may be related to the lack of toxicity for these amyloids. The mechanism of fibrillisation for functional amyloids has been reported to be dependent on changes to environmental conditions such as pH, temperature and solvent conditions. Some molecules are known to act as aggregation enhancers for functional amyloids, including, metal ions, heparin and lipid bilayer while others inhibit fibrillisation. Lipid membranes have been shown to significantly affect fibrillisation, and membrane- mediated fibrillisation has been well characterised for toxic amyloid species such as the amyloid-beta peptide involved in Alzheimer’s disease. Depending on the lipid composition and physicochemical properties of the membrane, lipid membranes can both promote or inhibit fibril growth. The following parameters, including a surface charge on the membrane, membrane fluidity, chain packing, and lipid solubility have been shown to drive changes in the electrostatic and hydrophobic interactions between the peptide and the membrane, and hence the rate of fibrillisation. However, essentially nothing is known about the membrane-mediated assembly of functional amyloid-forming peptides. In this thesis, the effect of the lipid membrane on fibrillisation of five different peptide hormones (Somatostatin, Oxytocin, Vasopressin, Substance P and Deslorelin) was investigated. In general, liposomes were used as model membranes. In Chapter 1, the effect of liposomes of different lipid composition on the fibrillisation of SST was investigated. SST reliably self-assembles into amyloid fibrils above a critical concentration (>5% w/w). Interactions of SST with the lipid bilayer were characterised using synchrotron radiation circular dichroism and intrinsic tryptophan fluorescence. The kinetics of fibrillisation was determined using a Thioflavin T assay, while the morphology of fibrils formed was directly visualised using atomic force microscopy (AFM). Reciprocal effects of the peptide and the growing fibril on the lipid bilayer were investigated using synchrotron small-angle x-ray scattering (SAXS). In Chapter 4 a similar suite of techniques was used to determine the effect of the lipid membrane on the fibrillisation of two additional cyclic peptides, the neurohypophysial hormone-like peptides, vasopressin (AVP-9) and oxytocin (OT-9). These two nine-amino acid peptides are likely to form aggregates due to mutations and are known to form functional VI amyloids in secretory granules. They are part of a family of structurally and functionally related peptide hormones with a conserved intramolecular ring, allowing us to determine whether substitutions in amino acids can impact the interactions of these peptides with the membrane and subsequent fibrillisation. In Chapter 5 the effect of linear vs cyclic peptides was determined using two linear peptides, substance P (SP), and Deslorelin (Des). Substance P has been reported to form fibrils and has also been observed to self-assemble into nanotubes. Deslorelin is an analogue of LHRH, which has also been shown to adopt nanotubes in solution. Finally, in Chapter 6, the anti-amyloidogenic effect of the polyphenol resveratrol, and its derivatives, Trimethoxy stilbene (TMS) and trans-stilbene (TS) was investigated using Somatostatin.
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