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Modification by glyceraldehyde-3-phosphate prevents amyloid transformation of alpha-synuclein

Kseniya Barinova, Marina Serebryakova, Evgeny Sheval, Elena Schmalhausen, Vladimir Muronetz
Biochimica et biophysica acta 2019 v.1867 no.4 pp. 396-404
Parkinson disease, aldehydes, amyloid, circular dichroism spectroscopy, diabetes, fluorescence, fluorescence emission spectroscopy, glyceraldehyde 3-phosphate, glyceraldehyde-3-phosphate dehydrogenase, glycolysis, intermediate product, metabolites, transmission electron microscopy
Numerous investigations point to the relation between diabetes and neurodegenerative disorders. Alpha-synuclein is a protein involved in the development of synucleinopathies including Parkinson's disease. In the present work, alpha-synuclein was for the first time modified by the intermediate product of glycolysis, glyceraldehyde-3-phosphate (GA-3-P). The resulting product was compared with the alpha-synuclein modified by methylglyoxal (MGO). The efficiency of the modification by the aldehydes was evaluated by decrease in free amino group content. The modification products were detected using fluorescence spectroscopy. The effect of modification by two glycating agents on the amyloid transformation of alpha-synuclein was investigated. Transmission electron microscopy analysis of the aggregates produced by the native alpha-synuclein under fibrillation conditions revealed the presence of 355–441-nm fibrils. In the aggregates produced by the modified alpha-synuclein, short fibrils of 65–230 nm or 85–260 nm were detected in the case of the protein treated with MGO and GA-3-P, respectively. Investigation of the aggregates by the fluorescence assay with Thioflavin T and CD spectroscopy showed that, in contrast to native alpha-synuclein, alpha-synuclein treated with GA-3-P does not produce real amyloid structures. Consequently, modification of alpha-synuclein by GA-3-P, the metabolite whose concentration is determined by the activity of glyceraldehyde-3-phosphate dehydrogenase, prevents its amyloid transformation.