Abstract
Amyloids are highly organized fibril aggregates arise from inappropriately folded form of the protein or polypeptide precursors under both physiological as well as simulated ambience. Amyloid synthesis is a multistep process that involves formation of several metastable intermediates. Among various intermediate species, the as-formed soluble oligomers are extremely toxic to the neuronal cells. In the present study, we evaluated cyclosporine A (CsA), an undecapeptide, for its potential to prevent aggregation of model protein ovalbumin (OVA). In an attempt to elucidate involved operative mechanism, the preliminary studies delineate that CsA affects both primary nucleation as well as other secondary pathways involved in OVA fibrillation process. By its specific interaction with amyloid intermediates, the cyclic peptide CsA seems to regulate the lag phase of the fibrillation process in concentration dependent manner. The present study further suggests that exposure to CsA during lag phase ensues in reversal of OVA fibrillation process. On the contrary, mature OVA fibril remained impervious to the CsA treatment. The cyclic undecapeptide CsA was also found to successfully alleviate amyloid induced toxicity in neuroblastoma cells.
Highlights
Aggregated forms of protein amyloids have a great deal of correlation with a growing list of diseases, including diabetes, Alzheimer’s, Parkinson’s, Huntington’s and Prion disease etc[1]
Thioflavin T (ThT) dye associated relative fluorescence intensity (RF intensity) has been used as a parameter to investigate the effect of cyclosporine A (CsA) on OVA fibril synthesis[37]
The ThT dye interacts with crossed-β sheet structure of as-synthesized fibril that eventually result in a significant rise in relative fluorescence intensity (RF value) of the binding complex (Fig. 1A)
Summary
Aggregated forms of protein amyloids have a great deal of correlation with a growing list of diseases, including diabetes, Alzheimer’s, Parkinson’s, Huntington’s and Prion disease etc[1]. The amyloid cascade hypothesis presumes that amyloid aggregates, self-assembled from misfolded Aβ peptides, affect the structure and function of neuronal cells and stimulate apoptosis[8,9]. This eventually results into synaptic dysfunction and neurodegeneration[10]. Recent advent in molecular biology and peptide synthesis technology has made it possible to fabricate specific peptides that have potential to inhibit aggregation While it remains to be seen whether short peptides can be exploited as therapeutic agents to prevent the amyloid related diseases, such inhibitors can help us to comprehend intricacies associated with protein aggregation process[14]. A dose of 100–500 ng/ml of CsA had been employed to study effect of CsA treatment on neurosphere cells[24]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
