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Exploring Mechanisms of Alpha-Synuclein Spread in Parkinson's and Atypical Parkinson's Diseases

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Exploring Mechanisms of Alpha-Synuclein Spread in Parkinson's and Atypical Parkinson's Diseases Exploring Mechanisms of Alpha-Synuclein Spread in Parkinson's and Atypical Parkinson's Diseases Author Valdinocci, Dario Published 2020-04-15 Thesis Type Thesis (PhD Doctorate) School School of Medical Science DOI https://doi.org/10.25904/1912/1951 Copyright Statement The author owns the copyright in this thesis, unless stated otherwise. Downloaded from http://hdl.handle.net/10072/393604 Griffith Research Online https://research-repository.griffith.edu.au PhD Thesis Exploring Mechanisms of Alpha-Synuclein Spread in Parkinson‟s and Atypical Parkinson‟s Diseases Student Name: Dario Valdinocci, BBiomedSc(Hons) s2843976 Principal Supervisor: Dr. Dean L. Pountney Associate Supervisor: A/Prof Gary Grant School of Medical Science Griffith University Gold Coast Submitted in fulfilment of the requirements of the degree of Doctor of Philosophy December 2019 Abstract The development of neurodegenerative diseases is an ever increasing risk faced by modern society as aging populations rise globally. For complex diseases such as Alzheimer‟s Disease (AD) or Parkinson‟s Disease (PD) the prospect of finding a cure within the immediate future is unlikely. These complexities arise primarily from the interactions of the protein of interest each of the diseases, which in the case of typical and atypical PD is α-synuclein (α-syn). Thought to be involved in neuronal vesicle recycling in its monomeric α-helical state, change to a β-sheet conformation allows α-syn to misfold, creating oligomers and eventually aggregates which form the initial bedrock for inclusion bodies. One of the more fascinating features of pathological α- syn is the difference in inclusion body composition and cell type affected in typical and atypical PD variants. For instance within Multiple System Atrophy (MSA), an atypical PD variant, α-syn aggregates form Glial Cytoplasmic Inclusions (GCIs) the composition of which differs from the Lewy Bodies (LB) formed in PD, and are largely found in oligodendrocytes. Unlike neurons, oligodendrocytes normally express only minimal amounts of α-syn which does not alter even after GCIs are formed, indicating acquisition of α-syn from an external source. How oligodendrocytes acquire pathological α-syn and the mechanisms by which the protein is able to spread within the central nervous system (CNS) are topics currently with more questions than answers. Thus the primary focus of the thesis is to investigate potential models of α-syn spread in order to develop future novel targets to slow disease progression. The investigations within Chapters 2 and 3 focus on exploring microglial cells as a potential vehicle for α-syn migration within the CNS. Along with the presence of α-syn inclusion bodies, part of the degeneration taking place within MSA is due to the chronic inflammatory activation and actions of the CNS resident immune cell, the microglia. Whilst microglial inflammatory responses play a role in PD, the severity of inflammation is greater in MSA. Microglia possess many traits which contribute to their ability to become a potential transporter of α-syn, including the lack of ability to degrade internalised pathological α-syn variants such as oligomers and aggregates. Post-mortem human MSA brain tissues were examined for evidence of microglial interactions with GCI-affected oligodendrocytes. Not only were interactions between these cells noted in a variety of different tissue regions and patients, but qualitative evidence of microglial migration with internalised α-syn distal from GCI-affected cells was obtained. Whilst these findings suggest that microglia could play a potential role in α-syn spread within the CNS and α-syn occurrence within oligodendrocytes, post-mortem examination is limited to detailing what may occur following the observed interactions. An in vitro assay was developed to investigate α-syn uptake and mobilisation by cells from a point source of immobilized protein. In this assay, monomeric and aggregated α-syn uptake and migration were assessed when exposured to THP-1 monocytes and microglial-like differentiated i THP-1 cells. Microglial-like differentiated THP-1 cells were found to show uptake and migration with internalised aggregate α-syn to distal regions, not observed with undifferentiated THP-1 monocytes or monomeric protein. This result indicates that microglia/microglial-like cells are more likely to internalise pathological α-syn such as aggregates than the normal, monomeric form. The greater numbers of differentiated THP-1 with internalised aggregated α- syn indicates that once the protein has been taken up by microglia, then it becomes a transported to distal brain regions. The inability of microglia to degrade aggregated α-syn, similar to microglia within the CNS, likely contributes microglial-mediated α-syn spread. Further testing using highly aggressive proliferating immortalised (HAPI) cells, a rat microglial cell line, was conducted which corroborated the previous findings, indicating that microglia take up the pathological variant of α-syn, mobilizing the protein rather than degrading it. Utilising the same α-syn mobilization assay, inhibition of microtubule instability through the use of the microtubule stabilising agent Epothilone D (EpoD) proved successful in lowering both uptake and mobilization of aggregated α-syn, showing promise as a novel therapy against α-syn spread. Inhibition of the microglial inflammatory response through TAK-242 treatment, a Toll-like Receptor 4 (TLR4) inhibitor, was also trialled to investigate if TLR4 plays a significant role with regards to α-syn uptake and mobilisation. However, unlike EpoD, TAK-242 proved ineffective. For Chapter 4 experimentation focussed on investigating the role of intercellular mitochondrial transfer through tunnelling nanotubes (TnTs) as a potential means of α-syn spread. Pathological α-syn species have been described to bind to intercellularly migrating organelles such as lysosomes for spread to adjacent sites. The role of mitochondria in typical and atypical PD has predominantly focussed on their role in degeneration and as such gaps exist as to mitochondrial function in relation to α-syn propagation. Utilising Stimulated Emission Depletion (STED) super resolution microscopy, SH-SY5Y, 1321N1 and differentiated THP-1 monocultures, as models of neurons, astrocytes and microglia, were each inoculated with aggregated α-syn to examine transfer to adjacent cells via TnTs whilst bound to mitochondria. Under each cell culture condition, the formation of TnT-like structures was observed between adjacent cells, each containing migrating mitochondria with α-syn aggregates bound to the outer mitochondrial membrane. Further exploration of this result through 1321N1 / differentiated THP-1 co-culture showed that this mechanism of α-syn spread is not limited to monoculture conditions and may be a potential mechanism relevant to typical and atypical PD. Knockdown of Miro1, a critical protein bridging mitochondria to the motor adaptor complex for intercellular migration, was performed in order to ascertain if its role is significant in the α-syn spread process and a potential therapeutic target. Miro1 silencing however proved qualitatively ineffective in the prevention of α-syn spread mediated by mitochondria, indicating other factors in addition to Miro1 may be involved in bridging mitochondria to intercellular motor complexes. Taken ii together these results illustrate the great complexity of mechanisms of α-syn spread and the inherent difficulties associated with attempting to combat them. iii Statement of Originality I, Dario Valdinocci, declare that this thesis entitled “Exploring Mechanisms of Alpha-Synuclein Spread in Parkinson’s and Atypical Parkinson’s Diseases” is of my own works and has not previously been submitted for a degree or diploma in any university. To the best of my knowledge and belief, the thesis contains no material previously published or written by another person except where due reference is made in the thesis itself. Dario Valdinocci December 2019 iv Contents List Abstract pg.i Statement of Originality pg.iv List of Figures pg.xi Publications During Candidacy pg.xiv Abbreviations pg.xix Acknowledgements pg.xxii Chapter 1: Introduction pg.1 1.1 Literature Review pg.2 1.1.1 Multiple System Atrophy pg.2 1.1.2 Alpha-Synuclein pg.4 1.1.2.1 Alpha-Synuclein in the Brain pg.4 1.1.2.2 Alpha-Synuclien in Disease pg.4 1.1.2.3 MSA as a Prion Disease pg.7 1.1.3 Microglia pg.8 1.1.3.1 Origin and Normal Role of Microglia pg.8 1.1.3.2 Iba-1 pg.11 1.1.3.3 Microglia in MSA pg.12 1.1.3.4 Toll-like Receptor 4 pg.15 1.1.3.5 Toll-like Receptor 4 and Its Role in Alpha Synucleinopathy pg.16 1.1.4 Transport pg.18 1.1.4.1 Extracellular Transport of Alpha Synuclein pg.18 1.1.4.2 Exosomes and Endocytosis pg.19 1.1.4.3 Tunnelling Nanotubes pg.21 1.1.4.4 Microglia as a Possible Transporter pg.23 v 1.1.4.5 Microtubules pg.25 1.1.4.6 Epothilones pg.26 1.1.5 Mitochondria pg.27 1.1.5.1 Mitochondria Normal Role pg.27 1.1.5.2 Role of Mitchondria in Neurons, Microglia and Astrocytes pg.31 1.1.5.3 Mitochondrial Transport pg.33 1.1.5.4 Role of Mitochondria in Synucleinopathies pg.35 1.2 Project Aims Overview pg.41 1.3 Specific Aims and Hypotheses pg.42 1.3.1 Chapter 2 - Epothilone D Inhibits Microglial-Mediated Spread of Alpha Synuclein Aggregates pg.42 1.3.1.1 Post-Mortem MSA Tissue Analysis pg.42 1.3.1.2 Alpha-Synuclein Mobilization Assay pg.42 1.3.1.3 Epothilone D Treatment pg.43 1.3.2 Chapter 3 - TAK-242 Has No Effect on Microglial Mediated Transport of Alpha Synuclein
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