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In-vitro and in-silico investigation of protective mechanisms of crocin against E46K α-synuclein amyloid formation

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Abstract

α-Synuclein is a presynaptic neuronal protein that is abundant in the human brain and is linked genetically and neuropathologically to Parkinson’s disease (PD). The E46K mutation of the α-synuclein gene has been linked to autosomal dominant early-onset of PD. Crocin is a carotenoid chemical compound of saffron that has been shown antioxidant and neural protective activity. This study examined the effect of Crocin in preventing the amyloid fibril in the E46K α-synuclein, through in vitro studies and computational simulations. The result demonstrated that Crocin acts as a molecular chaperone to prevent amyloid fibril formation of E46K α-synuclein in a concentration-dependent manner. In fact, Crocin redirects E46K α-synuclein from a fibril-formation pathway towards an amorphous aggregation pathway or at least reduce its aggregation tendency. Combined results from molecular dynamics and docking studies indicate that the inhibitory effect of the Crocin may be due to binding of the Crocin with the hydrophobic region (contact interface) of the α-synuclein which has the propensity to form amyloid aggregate. The results indicated Crocin can potentially bind to the C-terminal and mainly NAC (central hydrophobic region) domain of the E46K α-synuclein, and stabilizes the protein by masking the polymerization hotspot and consequently converting the protein into amyloid fibrils. These results support that Crocin is a effective inhibitor of E46K α-synuclein fibrillization and it could be considered as a potential therapeutic agent in the treatment of Parkinson disease.

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The authors are thankful to the university of Sistan and Baluchestan for providing necessary facilities.

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  1. Department of Biology, Faculty of Science, University of Sistan and Baluchestan, Zahedan, Iran

    Marzieh Ghasemi Tigan, Arezou Ghahghaei & Milad Lagzian

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  1. Marzieh Ghasemi Tigan
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Ghasemi Tigan, M., Ghahghaei, A. & Lagzian, M. In-vitro and in-silico investigation of protective mechanisms of crocin against E46K α-synuclein amyloid formation. Mol Biol Rep 46, 4279–4292 (2019). https://doi.org/10.1007/s11033-019-04882-9

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