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Quinolinic Acid Amyloid-like Fibrillar Assemblies Seed α-Synuclein Aggregation

Resource type
Date created
2018-08-08
Authors/Contributors
Author: Sade, Dorin
Author: Bera, Santu
Author: Gazit, Ehud
Abstract
Quinolinic acid (QA), a downstream neurometabolite in the kynurenine pathway, the biosynthetic pathway of tryptophan, is associated with neurodegenerative diseases pathology. Mutations in genes encoding kynurenine pathway enzymes, which control the level of QA production, are linked with elevated risk of developing Parkinson's disease. Recent findings have revealed the accumulation and deposition of QA in post-mortem samples, as well as in cellular models of Alzheimer's disease and related disorders. Furthermore, intrastriatal inoculation of mice with QA results in increased levels of phosphorylated α-synuclein and neurodegenerative pathological and behavioral characteristics. However, the cellular and molecular mechanisms underlying the involvement of QA accumulation in protein aggregation and neurodegeneration remain elusive. We recently established that self-assembled ordered structures are formed by various metabolites and hypothesized that these “metabolite amyloids” may seed amyloidogenic proteins. Here we demonstrate the formation of QA amyloid-like fibrillar assemblies and seeding of α-synuclein aggregation by these nanostructures both in vitro and in cell culture. Notably, α-synuclein aggregation kinetics was accelerated by an order of magnitude. Additional amyloid-like properties of QA assemblies were demonstrated using thioflavin T assay, powder X-ray diffraction and cell apoptosis analysis. Moreover, fluorescently labeled QA assemblies were internalized by neuronal cells and co-localized with α-synuclein aggregates. In addition, we observed cell-to-cell propagation of fluorescently labeled QA assemblies in a co-culture of treated and untreated cells. Our findings suggest that excess QA levels, due to mutations in the kynurenine pathway, for example, may lead to the formation of metabolite assemblies that seed α-synuclein aggregation, resulting in neuronal toxicity and induction of Parkinson's disease.
Document
Identifier
DOI: 10.1016/j.jmb.2018.08.002
Published as
Tavassoly, O., Sade, D., Bera, S., Shaham-Niv, S., Vocadlo, D. J., & Gazit, E. (2018). Quinolinic Acid Amyloid-like Fibrillar Assemblies Seed α-Synuclein Aggregation. Functional Amyloids in Health and Disease, 430(20), 3847–3862. https://doi.org/10.1016/j.jmb.2018.08.002.
Publication title
Functional Amyloids in Health and Disease
Document title
Quinolinic Acid Amyloid-like Fibrillar Assemblies Seed α-Synuclein Aggregation
Date
2018
Volume
430
Issue
20
First page
3847
Last page
3862
Copyright statement
Copyright is held by the author(s).
Scholarly level
Peer reviewed?
Yes
Language
English

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