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.
Highlights
The abnormal aggregation of α-synuclein (α-syn) in the central nervous system defines neurodegenerative diseases such as Parkinson’s disease (PD), Dementia with Lewy bodies (DLB) and Multiple system atrophy (MSA) (Spillantini and Goedert, 2000)
One could set up a hypothesis that in the situation where α-syn is bound to the membrane or is in the process of forming the α-helical structure, an aggregation-susceptible intermediate conformation could occur, which freely, unfolded monomeric α-syn could bind if available, resulting in abnormal aggregation (Figure 1)
The concentration of lipids could represent an additional intracellular factor that shifts the equilibrium of α-syn between an aggregation-prone intermediate conformation and its natively folded/unfolded state
Summary
The abnormal aggregation of α-synuclein (α-syn) in the central nervous system defines neurodegenerative diseases such as Parkinson’s disease (PD), Dementia with Lewy bodies (DLB) and Multiple system atrophy (MSA) (Spillantini and Goedert, 2000). This region further contains elements of the KTKEGV consensus sequence and together with the N-terminal domain, approximately two-thirds of the whole protein can form α-helices upon lipid binding. The most N-terminal α-helix (aa 6-25) anchored α-syn to the membrane surface with high affinity upon first contact, without being particular about lipid composition.
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