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Silica Nanoparticles Promote α-Synuclein Aggregation and Parkinson's Disease Pathology.

ABSTRACT: Silica nanoparticles (SiO₂ NPs) are increasingly investigated for their potential in drug delivery systems. However, the neurotoxicity of SiO₂ NPs remains to be fully clarified. Previously SiO₂ NPs have been reported to be detected in the central nervous system, especially in the dopaminergic neurons which are deeply involved in Parkinson's disease (PD). In this article, we characterized the effects of SiO₂ NPs on inducing PD-like pathology both in vitro and in vivo. Results showed that SiO₂ NPs promote more severe hyperphosphorylation and aggregation of α-synuclein, mitochondria impairment, oxidative stress, autophagy dysfunction, and neuronal apoptosis in the α-Syn A53T transgenic mice intranasally administrated with SiO₂ NPs compared with the control group. Our findings provide new evidence supporting that SiO₂ NPs exposure might have a strong capability of promoting the initiation and development of PD.

SUBMITTER: Yuan X

PROVIDER: S-EPMC8792744 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Silica Nanoparticles Promote α-Synuclein Aggregation and Parkinson's Disease Pathology.

Yuan Xin X Yang Yingxu Y Xia Danhao D Meng Lanxia L He Mingyang M Liu Chaoyang C Zhang Zhentao Z

Frontiers in neuroscience 20220113

Silica nanoparticles (SiO2 NPs) are increasingly investigated for their potential in drug delivery systems. However, the neurotoxicity of SiO2 NPs remains to be fully clarified. Previously SiO2 NPs have been reported to be detected in the central nervous system, especially in the dopaminergic neurons which are deeply involved in Parkinson's disease (PD). In this article, we characterized the effects of SiO2 NPs on inducing PD-like pathology both in ...[more]

PMID: 35095403

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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

Silica Nanoparticles Promote α-Synuclein Aggregation and Parkinson's Disease Pathology.

Publications

Silica Nanoparticles Promote α-Synuclein Aggregation and Parkinson's Disease Pathology.

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