The Role of Lipids in the Initiation of α-Synuclein Misfolding

Abstract

The aggregation of α-synuclein (α-syn) is inseparably connected to Parkinson's disease (PD). It is now well-established that certain forms of α-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 α-syn misfolding could help to explain why PD affects only some individuals and others not. Factors that chaperone the transition of α-syn's physiological to pathological function are of particular interest, since they offer opportunities for intervention. The relationship between α-syn and lipids represents one of those factors. Membrane interaction is crucial for normal cellular function, but lipids also induce the aggregation of α-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 α-syn interacts with lipids and how they can act as key factor for orchestrating toxic conversion of α-syn. Furthermore, we will discuss a scenario in which initial α-syn aggregation is determined by shifts in lipid/α-syn ratio as well as by dyshomeostasis of membrane bound/unbound state of α-syn.

Keywords: Parkisnon’s disease; alpha synuclein (α-syn); alpha synuclein accumulation; alpha synuclein oligomers; lipid turnover.

FIGURE 1

Schematic illustration of the discussed conformational states of α-syn. The unfolded, unbound and monomeric α-syn adopts a partially folded intermediate conformation at its very N-terminus upon membrane binding, leaving the NAC domain exposed for potential primary nucleation. Freely available monomeric α-syn could bind to the hypothesized intermediate conformation, facilitating initial lipid-induced amyloid oligomer and fibril formation. Under physiological conditions, α-syn quickly adopts an extended α-helical or a broken-helix conformation, which can also form physiological multimers that cluster synaptic vesicles. A change in the lipid/α-syn ratio, the lipid composition or the fraction of membrane bound vs. unbound α-syn could shift the balance between physiological and pathological paths.