Dataset Information

Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the ?-synuclein fibrils.

ABSTRACT: The aggregates of ?-synuclein (?S) are a major pathological hallmark of Parkinson's disease (PD) making their structure-function relationship important for rational drug design. Yet, the atomic structure of the ?S aggregates is unavailable, making it difficult to understand the underlying aggregation mechanism. In this work, based on available experimental data, we examined plausible molecular structures of ?S(20/30-110) fibrils for the first time by employing computational approaches. The optimized structure was used to investigate possible interactions with aggregation inhibitors. Our structural models characterize the essential properties of the five-layered fold of the ?S fibril. The distribution of the ?-strands and the topology of the five ?-strands in the relatively stable models are in good agreement with experimental values. In particular, we find that the KTK(E/Q)GV repeat motifs significantly stabilize the ?S fibrils. The charged residues within each repeat prefer exposure to the solvent in order to further stabilize the inter-layered interactions by salt-bridges. The organization of the repeat K(58)T(59)K(60)E(61)Q(62)V(63) between the ?2 and ?3 layers significantly affects the stability of the non-amyloid-component (NAC) domain. The coupling between the NAC domain and the KTKEGV repeats indicates that both regions can be potential binding sites for inhibitor design. The distinct binding modes of chemical agents that alter ?S aggregation highlight the potential of our models in inhibitor design.

SUBMITTER: Xu L

PROVIDER: S-EPMC4960003 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the α-synuclein fibrils.

Xu Liang L Nussinov Ruth R Ma Buyong B

European journal of medicinal chemistry 20160125

The aggregates of α-synuclein (αS) are a major pathological hallmark of Parkinson's disease (PD) making their structure-function relationship important for rational drug design. Yet, the atomic structure of the αS aggregates is unavailable, making it difficult to understand the underlying aggregation mechanism. In this work, based on available experimental data, we examined plausible molecular structures of αS(20/30-110) fibrils for the first time by employing computational approaches. The optim ...[more]

PMID: 26873872

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Project description:RationaleSynucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), share a distinct pathological feature, that is, a widespread accumulation of α-synuclein (α-syn) in the brain. There is a significant clinical unmet need for disease-modifying treatments for synucleinopathies. Recently, a seaweed-derived mixture of oligosaccharides sodium oligomannate, GV-971, was approved for Phase 2 clinical trials for PD. This study aimed to further evaluate the therapeutic effects of GV-971 on synucleinopathies using cellular and animal models and explore its associated molecular mechanisms.Methodsα-Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp-SNCAA53T mice, and brain slices from PD and DLB patients were used to determine the efficacy of GV-971 in ameliorating α-syn pathology. Measurements of motor functions, including pole, cylinder, and rotarod tests, were conducted on Prnp-SNCAA53T mice 4 weeks after intragastric administration of GV-971 (200 mg day-1 kg-1 ).ResultsGV-971 effectively prevented α-syn aggregation and even disassembled pre-aggregated α-syn fibrils, in vitro and ex vivo. In addition, GV-971 was able to rescue α-syn-induced neuronal damage and reduced release of extracellular vesicles (EVs), likely via modulating Alix expression. In the Prnp-SNCAA53T mouse model, when treated at the age of 5 months, GV-971 significantly decreased α-syn deposition in the cortex, midbrain, and cerebellum regions, along with ameliorating the motor dysfunctions.ConclusionsOur results indicate that GV-971, when administered at a relatively early stage of the disease process, significantly reduced α-syn accumulation and aggregation in Prnp-SNCAA53T mice. Furthermore, GV-971 corrected α-syn-induced inhibition of EVs release in neurons, contributing to neuronal protection. Future studies are needed to further assess GV-971 as a promising disease-modifying therapy for PD and other synucleinopathies.

Dataset Information

Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the ?-synuclein fibrils.

Publications

Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the α-synuclein fibrils.

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