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Lysosomal Ca Signalling and Neurodegeneration

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Lysosomal Ca Signalling and Neurodegeneration Lysosomal Ca 2+ Signalling and Neurodegeneration - A Global View Elizabeth Lucy Yates A thesis submitted for the degree of Doctor of Philosophy Department of Cell & Developmental Biology University College London May 2017 1 Declaration I, Elizabeth Yates, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Elizabeth Yates 2 Abstract Dysfunction of the lysosomal Ca 2+ channels TRPML1 and TPC2 has been implicated in neurodegenerative disease. However, there is little information about the involvement of these channels in cell-wide global Ca 2+ signalling and it is unknown whether their dysfunction contributes to neurodegeneration by disturbing it. First, by using synthetic compounds, I demonstrate that TRPML1 activation causes global Ca 2+ signals. In contrast with the predominant lysosomal localisation of the channel these Ca 2+ signals comprised a small lysosomal contribution and a large Ca 2+ entry component. Examination of TRPML1-mediated Fe 2+ entry posed the possibility that divalent cation entry can occur directly through TRPML1 on the plasma membrane. Second, I identified enlarged and clustered lysosomes in fibroblasts derived from people with sporadic Parkinson’s disease (PD). This was appropriately quantified from microscopy images by creating an automated sequence of image processing functions. By inhibiting TPC expression in fibroblasts I demonstrated their involvement in the propagation of physiological global Ca 2+ signals evoked by bradykinin. In sporadic and familial PD patient fibroblasts these TPC- dependent Ca 2+ signals were subtly modulated. Finally, in a neuronal cell line, reduced TPC expression inhibited the propagation of physiological global Ca 2+ signals evoked by carbachol. These Ca 2+ signals were also blocked by a recently identified TPC blocker and by putative TPC blockers that were screened by collaborators. In cells expressing the PD-associated mutant, LRRK2 G2019S, these TPC-dependent Ca 2+ signals were potentiated. In contrast, bradykinin-evoked Ca 2+ signals in this neuronal cell line were not inhibited by TPC blockers, nor were they potentiated in the LRRK2 G2019S cells. Therefore, physiological global Ca 2+ signalling in PD may be perturbed by TPC dysfunction, and be a compounding factor in neurodegeneration. Collectively this research suggests that lysosomal Ca 2+ signalling through TRPML1 and TPCs plays a role in global Ca 2+ signalling and that this may be disturbed in neurodegenerative disease. 3 Impact Statement Neurodegenerative diseases hit the headlines regularly in societies with ageing populations. There are few people who are not affected by them - either directly, as relatives or as carers. Devastating neurodegenerative disorders also affect young people and deny a quality of life that many take for granted. Academia, pharma, government health departments and charities are bracing for the increasing social and economic burden of these diseases for which there are currently no cures. Through endeavours to understand the cause of such diseases the lysosomes and lysosomal Ca 2+ channels such as TRPML1 and TPC2 have received mounting attention. Lysosomes store and release intracellular Ca 2+ which appears to be important for their own regulation. Ca 2+ release from the lysosomes can also cause increases to Ca 2+ levels throughout the cell. These global Ca 2+ signals may impact many critical Ca 2+ -sensitive processes and promote degeneration if they are disturbed. The global link between lysosomal Ca 2+ signalling and neurodegeneration has been the focus of this thesis. TRPML1 activation caused global Ca 2+ signals which were largely composed of Ca 2+ influx. These findings diverge from the perception that TRPML1 is a mediator of local Ca 2+ signalling. It may also have implications for how the channel is studied in the context of neurodegenerative disorders such as Mucolipidosis type IV and how its dysfunction is understood to be pathogenic. This data has been published as part of an open access article (Kilpatrick and Yates et al., 2016) and has been cited by a handful of works. Sporadic PD fibroblasts exhibited disturbed lysosome morphology. This adds weight to the idea that lysosomes have a role in PD. The image processing method used to quantify this defect has since been published in an open access article, and applied in the investigation of endolysosomal-ER contacts and growth factor signalling (Kilpatrick et al., 2017). Besides facilitating experimental work, this semi-automated image processing may be of use within a diagnostic assay for people presenting parkinsonian symptoms. This could enable timely administration of appropriate therapies. TPCs were required for physiological global Ca 2+ signalling. This supplements very limited data on this topic, and supports the notion that these channels may have cell-wide influence. Collaboration led to the identification of FDA-approved putative TPC blockers that inhibited physiological global Ca 2+ signals. The same signals were augmented in a neuronal PD model. This 4 poses the possibility that TPC dysfunction contributes to neurodegeneration via potentiated global Ca 2+ signalling. This could open up a new avenue for PD research and TPCs may emerge as suitable drug targets. Indeed, the putative TPC blockers may inform the development of PD- modifying drugs. The data in this thesis have been shared with a wide audience in the form of annual reports to Parkinson’s UK, publications, posters and talks. These have been presented at departmental seminars, the UCL Neuroscience Symposium, the International Meeting of the European Calcium Society, and a Parkinson’s UK visit attended by people with PD and their families. Data, ideas and tools presented in this thesis continue to be developed within the Patel laboratory. 5 Acknowledgments First, I would like to thank my supervisors Professor Sandip Patel and Professor Anthony Schapira for granting me the opportunity to study at UCL. Both have unbounded enthusiasm and drive to improve the lives of others through their research. In particular, I would like to thank Professor Sandip Patel for imparting his immense knowledge, for his continuous guidance and support, and for creating a research environment where ideas, methods and laughter are freely shared. I thank Parkinson’s UK for my funding. This charity truly brings science to life and it is difficult not to be inspired by their work, nor the people with Parkinson’s disease whom they involve in every aspect of what they do. To the individuals who donated skin biopsies for the fibroblast cultures used in this thesis - thank you. Likewise I acknowledge Henrietta Lacks and the girl whose cells have formed the HeLa and SH-SY5Y cell lines respectively. Numerous scientists have enabled my research, for which I am grateful. For this I extend my thanks to Drs Michelle Beavan, Alisdair McNeill, Jan-Willem Taanman and Tatiana Papkovskaia for generating the fibroblast cultures, to Drs Mark Cooper and Kai-Yin Chau for creating the stable LRRK2 SH-SY5Y cell lines, to Dr Stephen Mullin for murine neurons and Drs Taufiq Rahman, Christopher Penny and Prof Patel for their identification of putative TPC inhibitors. I would also like to recognise my graduate tutor Professor Michael Duchen, Dr Andrey Abramov and Professor Gyorgy Szabadkai for formative and stimulating discussion about my work, particularly on the topic of lysosome morphology quantification. I also thank Dr Bill Andrews for his technical advice on quantitative PCR. To Dr Bethan Kilpatrick and Leanne Hockey, who showed me the ropes when I joined the Patel lab and beyond - your time, expertise and patience cannot be underestimated. To you, and Dr Alice Roycroft, Cara Yuan, Dr Christopher Penny, Dr Manuela Melchionda and Dr Sophie McLachlan, with whom I’ve shared an office for 3 years - thank you all for your technical support, your camaraderie and the endless baked goods, for which I have been reprimanded by the dentist. Thanks also to Dr Lewis Brayshaw, who as a chatty resident of the culture room provided light relief between cell counts, and similarly to Adam Shellard in the office next door, who truly sings “like no one is listening”. Finally, to my friends and family outside UCL life - your support and encouragement has been tremendous, and an essential part of this thesis. Thank you. 6 Contents Declaration ................................................................................................................................... 2 Abstract ........................................................................................................................................ 3 Impact Statement ......................................................................................................................... 4 Acknowledgments ........................................................................................................................ 6 Abbreviations ............................................................................................................................. 15 CHAPTER 1: Introduction ........................................................................................................... 18 1.1 OVERVIEW ......................................................................................................................... 18 1.2 LYSOSOMES ......................................................................................................................
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