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The aggregation of a-synuclein (a-syn) is inseparably connected to Parkinson’s disease (PD). It is now well-established that certain forms of a-syn aggregates, oligomers and fibrils, can exert neurotoxicity in synucleinopathies. With the exception of rare familial forms, the vast majority of PD cases are idiopathic. Understanding the earliest molecular mechanisms that cause initial a-syn misfolding could help to explain why PD affects only some individuals and others not. Factors that chaperone the transition of a-syn’s physiological to pathological function are of particular interest, since they offer opportunities for intervention. The relationship between a-syn and lipids represents one of those factors. Membrane interaction is crucial for normal cellular function, but lipids also induce the aggregation of a-syn, causing cell toxicity. Also, disease-causing or risk-factor mutations in genes related to lipid metabolism like PLA2G6, SCARB2 or GBA1 highlight the close connection between PD and lipids. Despite the clear link, the ambivalent interaction has not been studied sufficiently so far. In this review, we address how a-syn interacts with lipids and how they can act as key factor for orchestrating toxic conversion of a-syn. Furthermore, we will discuss a scenario in which initial a-syn aggregation is determined by shifts in lipid/a-syn ratio as well as by dyshomeostasis of membrane bound/unbound state of a-syn., publishedVersion

Several age-related neurodegenerative disorders are associated with protein misfolding and aggregation of toxic peptides. α-synuclein (α-syn) aggregation and the resulting cytotoxicity is a hallmark of Parkinson's disease (PD) as well as dementia with Lewy bodies. Rising evidence points to oligomeric and pre-fibrillar forms as the pathogenic species, and oligomer secretion seems to be crucial for the spreading and progression of PD pathology. Recent studies implicate that dysfunctions in endolysosomal/autophagosomal pathways increase α-syn secretion. Mutation in the retromer-complex protein VPS35, which is involved in endosome to Golgi transport, was suggested to cause familial PD. GGA proteins regulate vesicular traffic between Golgi and endosomes and might work as antagonists for retromer complex mediated transport. To investigate the role of the GGAs in the α-syn oligomerization and/or secretion process we utilized protein-fragment complementation assays (PCA). We here demonstrate that GGAs alter α-syn oligomer secretion and α-syn oligomer-mediated toxicity. Specifically, we determined that GGA3 modifies extracellular α-syn species in an exosome-independent manner. Our data suggest that GGA3 drives α-syn oligomerization in endosomal compartments and thus facilitates α-syn oligomer secretion. Preventing the early events in α-syn oligomer release may be a novel approach to halt disease spreading in PD and other synucleinopathies.

Objective Excessive inflammation in the central nervous system (CNS) and the periphery can result in neurodegeneration and parkinsonism. Recent evidence suggests that immune responses in Parkinson disease patients are dysregulated, leading to an increased inflammatory reaction to unspecific triggers. Although �����synuclein pathology is the hallmark of Parkinson disease, it has not been investigated whether pathologic �����synuclein is a specific trigger for excessive inflammatory responses in Parkinson disease. Methods We investigated the immune response of primary human monocytes and a microglial cell line to pathologic forms of �����synuclein by assessing cytokine release upon exposure. Results We show that pathologic �����synuclein (mutations, aggregation) results in a robust inflammatory activation of human monocytes and microglial BV2 cells. The activation is conformation��� dependent, with increasing fibrillation and early onset mutations having the strongest effect on immune activation. We also found that activation of immune cells by extracellular �����synuclein is potentiated by extracellular vesicles, possibly by facilitating the uptake of �����synuclein. Blood extracellular vesicles from Parkinson disease patients induce a stronger activation of monocytes than blood extracellular vesicles from healthy controls. Most importantly, monocytes from Parkinson disease patients are dysregulated and hyperactive in response to stimulation with pathologic �����synuclein. Furthermore, we demonstrate that �����synuclein pathology in the CNS is sufficient to induce the monocyte dysregulation in the periphery of a mouse model. Interpretation Taken together, our data suggest that �����synuclein pathology and dysregulation of monocytes in Parkinson disease can act together to induce excessive inflammatory responses to �����synuclein. ANN NEUROL 2019;86:593���606, publishedVersion