Quinolinic Acid Amyloid-like Fibrillar Assemblies Seed α-Synuclein Aggregation. Issue 20 (12th October 2018)

• Record Type: Journal Article
• Authors: Tavassoly, Omid; Sade, Dorin; Bera, Santu; Shaham-Niv, Shira; Vocadlo, David J.; Gazit, Ehud
• Is Part Of: Journal of molecular biology. Volume 430:Issue 20(2018)
• Page Start: 3847
• Page End: 3862
• Publication Date: 2018-10-12
• Subjects: metabolite amyloid -- quinolinic acid -- cross-seeding -- α-synuclein -- Parkinson's disease; AD Alzheimer's disease -- PD Parkinson's disease -- ACMSD 2-amino-3-carboxymuconic semialdehyde decarboxylase -- PA picolinic acid -- QPRTase quinolinate phosphoribosyltransferase -- TEM transmission electron microscopy -- PXRD powder X-ray diffraction -- EGCG epigallocatechin gallate -- PI propidium iodide -- BSA bovine serum albumin -- CD circular dichroism -- FBS fetal bovine serum -- QA quinolinic acid; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2018.08.002
• Languages: English
• ISSNs: 0022-2836

Abstract

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. Graphical Abstract: Highlights: Quinolinic acid, a neurometabolite that accumulates in neurodegenerative diseases, forms nano-scale amyloid-like fibrillar structures. Quinolinic acid assemblies may explain the initial steps inducing α-synuclein aggregation. Quinolinic acid assemblies are taken up by cells, co-localize with α-synuclein aggregates and seed the aggregation of α-synuclein monomers.