Hays Watson, Aurelia; (2024) The impact of lipid droplets on α-synuclein protein folding and aggregation propensities in Parkinson’s disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Synucleinopathies, including Parkinson’s Disease (PD) are a group of neurodegenerative diseases charac- terised by the presence of Lewy Bodies (LB), insoluble α-synuclein (aSyn) positive inclusions, in the brain. Recent studies show membranous structures are present in the core of LB pathology and numerous groups have highlighted the important role lipids play in the context-dependent folding of aSyn. However, lipid droplets (LD), which are active regulators in lipid homeostasis and a core feature of membranous LB, remain understudied in neurodegeneration. LD consist of a neutral lipid core encased by a mono-phospholipid layer. They have been shown to increase with age and cellular stress, and crucially that they interact with aSyn. Nevertheless, mechanistic insight into the role that LD play in synucleinopathies remains elusive. Here, we aim to characterise aSyn-LD interaction and determine how this might impact pathology progression. To do this we use a range of molecular and cellular techniques. Our results confirm that LD are direct binding partners of aSyn. In cell culture, excessive aSyn-LD interaction, driven by oleic acid treatment, leads to the development of pathological phenotypes including phosphorylated-aSyn. Furthermore, circular dichro- ism (CD) spectroscopy demonstrates that LD misfold aSyn compared to synthetic vesicles. This appears to facilitate spontaneous aSyn aggregation as detected on a seed amplification assay (SAA). Importantly, we also generate artificial LD (aLD), with a customizable neutral lipid core as determined by human brain lipidomics. We show that aLD drive potent fibril formation, which more closely mimic human brain-derived bioactivity than synthetic aggregates obtained without lipids. The mechanistic insight laid out here suggests a hypothesis of LD-driven strain formation and prion-like spread. These findings provide novel insights into LD accumulation as a potential PD aetiology and identify LD turnover as a possible therapeutic target. Moreover, our aLD-derived fibrils offer a notable improvement to the current PFF recombinant PD model.

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