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.

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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