Abstract
α-Synuclein (αS) is a presynaptic protein whose aggregation is associated with Parkinson’s disease (PD). Although the physiological function of αS is still unclear, several lines of evidence indicate that this protein may play a role in the trafficking of synaptic vesicles (SVs) during neurotransmitter release, a task associated with its ability to bind SVs and promote their clustering. It is therefore crucial to identify the cellular factors that modulate this process. To address this question, using nuclear magnetic resonance (NMR) spectroscopy we have characterized the role of cholesterol, a major component of the membrane of SVs, in the binding of αS with synaptic-like vesicles. Our results indicate that cholesterol can act as a modulator of the overall affinity of αS for SVs by reducing the local affinity of the region spanning residues 65–97 in the non-amyloid-β component (NAC) of the protein. The increased population of bound states that expose the region 65–97 to the solvent was found to induce stronger vesicle-vesicle interactions by αS. These results provide evidence that cholesterol modulates the clustering of synaptic vesicles induced by (α)S, and supports the role of the disorder-to-order equilibrium of the NAC region in the modulation of the biological properties of the membrane-bound state of αS.
Highlights
Our results indicate that cholesterol can act as a modulator of the overall affinity of αS for synaptic vesicles (SVs) by reducing the local affinity of the region spanning residues 65–97 in the non-amyloid-β component (NAC) of the protein
Genetic links exist between αS and Parkinson’s disease (PD), with point mutations, duplication and triplications in the αS encoding gene being associated with familial forms of the disease (Polymeropoulos et al, 1997; Kruger et al, 1998; Singleton et al, 2003; Zarranz et al, 2004; AppelCresswell et al, 2013; Lesage et al, 2013). αS aggregates have been found in other neurodegenerative disorders, including Alzheimer’s disease (Lewis et al, 2010), dementia with Lewy bodies (Galvin et al, 1999), multiple system atrophy (Spillantini et al, 1998), and other synucleinopathies (Chiti and Dobson, 2017)
We used synaptic-like small unilamellar vesicles (SUVs) composed of a mixture of 1,2-dioleoyl-sn-glycero-3
Summary
A common characteristics of the majority of the putative functions so far proposed for αS – including SV trafficking (Wislet-Gendebien et al, 2006; Gitler et al, 2008; Soper et al, 2008; Auluck et al, 2010; Burre et al, 2010, 2014; Diao et al, 2013), ER-to-Golgi vesicle trafficking (Cooper et al, 2006; Gitler et al, 2008), mitochondrial binding (Zigoneanu et al, 2012; Maltsev et al, 2013; Menges et al, 2017) – involves the binding with biological membranes (Zigoneanu et al, 2012; Maltsev et al, 2013; Snead and Eliezer, 2014). The partition between membrane bound and unbound states of αS appears to be highly regulated in vivo (Lee et al, 2002) and influences its aggregation propensity (Perrin et al, 2001; Necula et al, 2003; Sharon et al, 2003; Zhu and Fink, 2003; Auluck et al, 2010; Comellas et al, 2012)
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