Abstract
SummaryThe aberrant aggregation of α-synuclein is associated with several human diseases, collectively termed the α-synucleinopathies, which includes Parkinson’s disease. The progression of these diseases is, in part, mediated by extracellular α-synuclein oligomers that may exert effects through several mechanisms, including prion-like transfer, direct cytotoxicity, and pro-inflammatory actions. In this study, we show that two abundant extracellular chaperones, clusterin and α2-macroglobulin, directly bind to exposed hydrophobic regions on the surface of α-synuclein oligomers. Using single-molecule fluorescence techniques, we found that clusterin, unlike α2-macroglobulin, exhibits differential binding to α-synuclein oligomers that may be related to structural differences between two previously described forms of αS oligomers. The binding of both chaperones reduces the ability of the oligomers to permeabilize lipid membranes and prevents an oligomer-induced increase in ROS production in cultured neuronal cells. Taken together, these data suggest a neuroprotective role for extracellular chaperones in suppressing the toxicity associated with α-synuclein oligomers.
Highlights
The a-synucleinopathies are a group of progressive and, fatal neurodegenerative disorders, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA)
We have recently shown that this process is sufficient to protect cultured neuronal cells and Drosophila melanogaster from proteotoxicity associated with the aggregation of the amyotrophic lateral sclerosis (ALS)-linked protein TDP-43 (Gregory et al, 2017)
We first performed two-color coincidence detection (TCCD) measurements to explore the interaction of the Extracellular chaperones (ECs) with aS during the aggregation process
Summary
The a-synucleinopathies are a group of progressive and, fatal neurodegenerative disorders, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). AS oligomers undergo a structural conversion from a relatively unstable species to more stable and compact oligomers that have increased cytotoxicity and resistance to proteinase-K degradation compared to the preceding oligomers (Cremades et al, 2012; Horrocks et al, 2015; Iljina et al, 2016). This conversion occurs before the oligomers are incorporated into fibrillar structures and is a critical step in the aggregation pathway of aS. Direct neurotoxicity of extracellular aS has been observed, which could be caused by the unregulated insertion of aS aggregates into cell membranes and/or neuroinflammatory responses such as microglia activation and generation of intracellular reactive oxygen species (ROS) (Cremades et al, 2012; Fusco et al, 2017; Reynolds et al, 2011; Zhang et al, 2005)
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