Bilberry Anthocyanins Neutralize the Cytotoxicity of Co-Chaperonin GroES Fibrillation Intermediates

Abstract

The co-chaperonin GroES (Hsp10) works with chaperonin GroEL (Hsp60) to facilitate the folding reactions of various substrate proteins. Upon forming a specific disordered state in guanidine hydrochloride, GroES is able to self-assemble into amyloid fibrils similar to those observed in various neurodegenerative diseases. GroES therefore is a suitable model system to understand the mechanism of amyloid fibril formation. Here, we determined the cytotoxicity of intermediate GroES species formed during fibrillation. We found that neuronal cell death was provoked by soluble intermediate aggregates of GroES, rather than mature fibrils. The data suggest that amyloid fibril formation and its associated toxicity toward cell might be an inherent property of proteins irrespective of their correlation with specific diseases. Furthermore, with the presence of anthocyanins that are abundant in bilberry, we could inhibit both fibril formation and the toxicity of intermediates. Addition of bilberry anthocyanins dissolved the toxic intermediates and fibrils, and the toxicity of the intermediates was thus neutralized. Our results suggest that anthocyanins may display a general and potent inhibitory effect on the amyloid fibril formation of various conformational disease-causing proteins.

Antioxidant and proapoptotic effects of anthocyanins from bilberry extract in rats exposed to hepatotoxic effects of carbon tetrachloride

“…Bilberry encompasses 15 different anthocyanins which represent combinations of five anthocyanidins (delphinidin, cyanidin, peonidin, petunidin, and malvidin) and three sugary components (3-O-arabinoside, 3-Oglucoside, and 3-O-galactoside) [4,5]. Many studies have shown that bilberry has the hypoglycemic and hypolipidemic effects, improves night vision, slows down the development of diabetic retinopathy, and prevents the creation of amyloid fibrils, which is why it can be used in treating the neurodegenerative diseases [6,4,7]. Anthocyanins from bilberry express significant antioxidative, anti-inflammatory, anticancerogenic, antiatherosclerotic, antimicrobial and antiulcer activities [2,8,9].…”

Suppression of amyloid fibrils using the GroEL apical domain

“…The isolated apical domain was used to modulate the fibrillogenesis of three target peptides (Aβ42, α-Synuclein, and GroES). All three polypeptides have either been implicated in the pathogenesis of various diseases, or displayed cytotoxic tendencies in previous experiments 50 .…”

“…GroES has not been implicated in the pathogenesis of any specific diseases to date; however, preparations of GroES have been shown to form characteristic amyloid fibrils under denaturing conditions such as moderate concentrations of Gdn-HCl 49 . Interestingly, intermediate oligomeric forms of GroES that are formed during fibrillogenesis display cytotoxicity toward cultured mouse neuron cells 50 . As shown in Fig.…”

Disaggregation Behavior of Amyloid β Fibrils by Anthocyanins Studied by Total-Internal-Reflection-Fluorescence Microscopy Coupled with a Wireless Quartz-Crystal Microbalance Biosensor

“…Recently, it is found that anthocyanins can be promising candidates for inhibiting the fibril formation and suppressing the neurotoxicity of amyloid fibrils. − This finding is considerably important because they are flavonoid pigments which induce red, blue, and purple colors in fruits and vegetables, and we can easily ingest them ordinarily. Their inhibitory effects on AD have been indicated in vivo , and in cells as well as their beneficial effects on health such as antioxidant activity. − The inhibitory ability has been evaluated macroscopically through the thioflavin-T (ThT) fluorescence assay, where the ThT fluorescence level was monitored during the aggregation reactions of amyloidogenic proteins.…”

“…In this study, we focus on three galactosides [delphinidin-3-galactoside (D3-gal), cyanidine-3-galactoside (C3-gal), and malvidin-3-galactoside (M3-gal)] among them because of three reasons: (i) they tend to accumulate in tissues, especially in the cerebellum, so that they may directly affect neurodegenerative diseases. (ii) It is suggested that D3-gal and C3-gal show inhibitor ability to the formation of amyloid fibrils . (iii) Their concentrations are relatively larger in berries, which can be ingested orally.…”