Dataset Information

Multi-Pronged Interactions Underlie Inhibition of ?-Synuclein Aggregation by ?-Synuclein.

ABSTRACT: The intrinsically disordered protein ?-synuclein is known to inhibit the aggregation of its intrinsically disordered homolog, ?-synuclein, which is implicated in Parkinson's disease. While ?-synuclein itself does not form fibrils at the cytoplasmic pH?7.4, alteration of pH and other environmental perturbations are known to induce its fibrilization. However, the sequence and structural determinants of ?-synuclein inhibition and self-aggregation are not well understood. We have utilized a series of domain-swapped chimeras of ?-synuclein and ?-synuclein to probe the relative contributions of the N-terminal, C-terminal, and the central non-amyloid-? component domains to the inhibition of ?-synuclein aggregation. Changes in the rates of ?-synuclein fibril formation in the presence of the chimeras indicate that the non-amyloid-? component domain is the primary determinant of self-association leading to fibril formation, while the N- and C-terminal domains play critical roles in the fibril inhibition process. Our data provide evidence that all three domains of ?-synuclein together contribute to providing effective inhibition, and support a model of transient, multi-pronged interactions between IDP chains in both processes. Inclusion of such multi-site inhibitory interactions spread over the length of synuclein chains may be critical for the development of therapeutics that are designed to mimic the inhibitory effects of ?-synuclein.

SUBMITTER: Williams JK

PROVIDER: S-EPMC6100766 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Multi-Pronged Interactions Underlie Inhibition of α-Synuclein Aggregation by β-Synuclein.

Williams Jonathan K JK Yang Xue X Atieh Tamr B TB Olson Michael P MP Khare Sagar D SD Baum Jean J

Journal of molecular biology 20180518 16

The intrinsically disordered protein β-synuclein is known to inhibit the aggregation of its intrinsically disordered homolog, α-synuclein, which is implicated in Parkinson's disease. While β-synuclein itself does not form fibrils at the cytoplasmic pH 7.4, alteration of pH and other environmental perturbations are known to induce its fibrilization. However, the sequence and structural determinants of β-synuclein inhibition and self-aggregation are not well understood. We have utilized a series o ...[more]

PMID: 29782835

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Project description:In neurodegenerative diseases, it remains unclear why certain brain regions are selectively vulnerable to protein aggregation. In transgenic mice expressing human A53T ?-synuclein, the brainstem and spinal cord develop the most prominent ?-synuclein inclusions which correlate with age-dependent motor dysfunction. Herein we present the novel finding that this selective aggregation is in part dependent on the inability of chaperone-mediated autophagy (CMA) to effectively degrade ?-synuclein in these brain regions. Lysosomal assays revealed that CMA activity was significantly decreased in aggregation-prone regions compared to the remainder of the brain. Previously, CMA activity has been shown to be proportional to levels of the CMA receptor Lamp-2a. Using antibodies, brain tissue from Lamp-2a null mice, enzymatic deglycosylation, and mass spectrometry, we identified Lamp2a as a novel 72kDa glycoprotein in the mouse brain. Examination of Lamp-2a levels revealed differences in expression across brain regions. The brainstem and the spinal cord had a more than three-fold greater levels of Lamp-2a as compared to regions less vulnerable to aggregation and exhibited a selective upregulation of Lamp-2a during development of ?-synuclein inclusions. Despite this dynamic response of Lamp-2a, the levels of substrates bound to the brain lysosomes as well as the rates of substrate uptake and degradation were not proportional to the levels of Lamp-2a. These regional differences in CMA activity and Lamp-2a expression were found in both non-transgenic mice as well as A53T ?-syn mice. Therefore, these are inherent variations and not a transgene-specific effect. However, differences in CMA activity may render select brain regions vulnerable to homeostatic dysfunction in the presence of stressors such as overexpression of human A53T ?-syn. Collectively, the data provide a potential mechanism to explain the dichotomy of vulnerability or resistance that underlies brain regions during aggregate formation in neurodegenerative disease.

Project description:While several polyphenols were found to either inhibit or modulate the aggregation of proteins implicated in neurodegenerative diseases, such as Parkinson's disease (PD), discrepant action mechanisms have been reported. This, in addition to some polyphenols' pan-assay interference compounds' reputation, casts some doubts concerning their therapeutic relevance. Here, we studied, through molecular dynamics and enhanced sampling methods, the aggregation of 11-mer peptides from the non-amyloid-β component, an aggregation-prone domain of α-synuclein (α-syn) implicated in PD and other synucleinopathies, in neat water and aqueous solutions of resveratrol (RSV) and gallic acid (GA). Further, simulations of the complete protein were carried out in aqueous urea, RSV, and GA solutions. Our results show that peptide aggregation is not disrupted by either phenolic compound. Thus, instead, intrusion of RSV and GA in the inter-peptide region induces a peptide-peptide re-orientation, favoring terminal interactions that manifest in the formation of barrierless solvent-separated configurations. Moreover, although the (poly)phenols induce a pronounced peptide dewetting at high concentrations, β-sheet-rich regions, a hallmark of α-syn aggregation, are not disrupted. Thus, our results indicate that, if anything, RSV and GA delay or modulate peptide aggregation at high concentrations via the stabilization of solvent-separated conformations as opposed to aggregation inhibition. Structural analysis of the full protein, however, shows that the (poly)phenols induce more extended conformations of α-syn, similar to urea, possibly also influencing its aggregation propensity. However, opposite to urea, the (poly)phenols reduce α-syn's conformational space, likely due to steric effects and a slowdown of the solvent dynamics. These effects are concentration-dependent and possibly unattainable at therapeutic-relevant concentrations. These results suggest that the aggregation inhibition activity of RSV and GA in vitro should involve, instead, either the non-covalent binding to oligomeric intermediates or the stabilization of the monomer and/or oligomers through the formation of covalent bonds of the respective quinones with α-syn. In addition, the enhanced aggregation tendency of the peptides observed here could be associated with the formation of non-toxic oligomers, reported for some polyphenols.

Dataset Information

Multi-Pronged Interactions Underlie Inhibition of ?-Synuclein Aggregation by ?-Synuclein.

Publications

Multi-Pronged Interactions Underlie Inhibition of α-Synuclein Aggregation by β-Synuclein.

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