Astrocyte and monocyte contributions to neuronal alpha-synuclein pathology in Parkinson’s disease
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Type
ThesisThesis type
Doctor of PhilosophyAuthor/s
Weiss, Fiona CeciliaAbstract
Parkinson’s disease (PD) is a progressive neurodegenerative disease characterised by the loss of dopaminergic (DA) neurons and the abnormal deposition of Lewy bodies enriched with aggregated α-synuclein (α-syn). Neuroinflammation is associated with PD pathogenesis with activated ...
See moreParkinson’s disease (PD) is a progressive neurodegenerative disease characterised by the loss of dopaminergic (DA) neurons and the abnormal deposition of Lewy bodies enriched with aggregated α-synuclein (α-syn). Neuroinflammation is associated with PD pathogenesis with activated glial cells and infiltrating monocytes in the PD brain. Aggregated α-syn is reported to activate toll-like receptors (TLRs) in glial cells and monocytes, likely contributing to PD pathology. However, the role of TLR2 in DA neurons has not been previously reported, and the contribution of TLR2 activated astrocytes and monocytes in α-syn aggregation and DA neuron loss is less explored in human models of disease. The current thesis aimed to optimise induced pluripotent stem cell (iPSC) derived models of PD to investigate the role of TLR2 signalling in DA neuron degeneration. TLR2 activation in iPSC-derived DA neurons lead to an increase α-syn accumulation, but no loss of DA neurons was observed. Thus, an iPSC derived midbrain model involving astrocytes and DA neurons was optimised to determine the contribution of astrocytic TLR2 activation in DA neuronal loss. In PD derived midbrain cells TLR2 activation led to autophagy inhibition and potentiated α-syn aggregation seeded by preformed fibrils. Astrocytes also displayed autophagy impairment, α-syn aggregation and a pro-inflammatory A1 phenotype, contributing to the specific loss of DA neurons. To further study the contribution of TLR-activated monocytes in PD, primary monocytes were activated by the treatment of TLR2 agonist Pam3CSK4 or TLR4 agonist lipopolysaccharide and added to co-culture with midbrain cells. Only TLR2 activated monocytes led to an increase in neuronal α-syn and astrocytic autophagy inhibition, while TLR4 activated monocytes induced astrogliosis. DA neuron degeneration was observed in co-culture with both TLR2 and TLR4 activated monocytes. Overall, this thesis confirms a role for TLR mediated inflammation in PD progression.
See less
See moreParkinson’s disease (PD) is a progressive neurodegenerative disease characterised by the loss of dopaminergic (DA) neurons and the abnormal deposition of Lewy bodies enriched with aggregated α-synuclein (α-syn). Neuroinflammation is associated with PD pathogenesis with activated glial cells and infiltrating monocytes in the PD brain. Aggregated α-syn is reported to activate toll-like receptors (TLRs) in glial cells and monocytes, likely contributing to PD pathology. However, the role of TLR2 in DA neurons has not been previously reported, and the contribution of TLR2 activated astrocytes and monocytes in α-syn aggregation and DA neuron loss is less explored in human models of disease. The current thesis aimed to optimise induced pluripotent stem cell (iPSC) derived models of PD to investigate the role of TLR2 signalling in DA neuron degeneration. TLR2 activation in iPSC-derived DA neurons lead to an increase α-syn accumulation, but no loss of DA neurons was observed. Thus, an iPSC derived midbrain model involving astrocytes and DA neurons was optimised to determine the contribution of astrocytic TLR2 activation in DA neuronal loss. In PD derived midbrain cells TLR2 activation led to autophagy inhibition and potentiated α-syn aggregation seeded by preformed fibrils. Astrocytes also displayed autophagy impairment, α-syn aggregation and a pro-inflammatory A1 phenotype, contributing to the specific loss of DA neurons. To further study the contribution of TLR-activated monocytes in PD, primary monocytes were activated by the treatment of TLR2 agonist Pam3CSK4 or TLR4 agonist lipopolysaccharide and added to co-culture with midbrain cells. Only TLR2 activated monocytes led to an increase in neuronal α-syn and astrocytic autophagy inhibition, while TLR4 activated monocytes induced astrogliosis. DA neuron degeneration was observed in co-culture with both TLR2 and TLR4 activated monocytes. Overall, this thesis confirms a role for TLR mediated inflammation in PD progression.
See less
Date
2023Rights statement
The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.Faculty/School
Faculty of Medicine and Health, School of Medical SciencesAwarding institution
The University of SydneyShare