The aggregation of the protein alpha synuclein (α-Syn), a known contributor in Parkinson's disease (PD) pathogenesis is triggered by transition metal ions through occupational exposure and disrupted metal ion homeostasis. Naturally occurring small molecules such as polyphenols have emerged as promising inhibitors of α-Syn fibrillation and toxicity and could be potential therapeutic agents against PD. Here, using an array of biophysical tools combined with cellular assays, we demonstrate that the novel polyphenolic compound scutellarin efficiently inhibits the uninduced and metal-induced fibrillation of α-Syn by acting at the nucleation stage and stabilizes a partially folded intermediate of α-Syn to form SDS-resistant, higher-order oligomers (∼680 kDa) and also disaggregates preformed fibrils of α-Syn into similar type of higher-order oligomers. ANS binding assay, fluorescence lifetime measurements and cell-toxicity experiments reveal scutellarin-generated oligomers as compact, low hydrophobicity structures with modulated surface properties and significantly reduced cytotoxicity than the fibrillation intermediates of α-Syn control. Fluorescence spectroscopy and isothermal titration calorimetry establish the binding between scutellarin and α-Syn to be non-covalent in nature and of moderate affinity (Ka ∼ 105 M−1). Molecular docking approaches suggest binding of scutellarin to the residues present in the NAC region and C-terminus of monomeric α-Syn and the C-terminal residues of fibrillar α-Syn, demonstrating inhibition of fibrillation upon binding to these residues and possible stabilization of the autoinhibitory conformation of α-Syn. These findings reveal interesting insights into the mechanism of scutellarin action and establish it as an efficient modulator of uninduced as well as metal-induced α-Syn fibrillation and toxicity.
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February 2020
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Cover Image
The cover image shows the substrate and inhibitor binding to the human biliverdin IXβ reductase active site; crystallographic structures of the ternary complexes of BLVRB with NADP+ and the substrate mesobiliverdin IVα and the inhibitor phloxine B are shown. For more information, see the article by Zhang and colleagues on pp. 601–614. Image provided by Wadie Bahou.
Research Article|
February 11 2020
Scutellarin inhibits the uninduced and metal-induced aggregation of α-Synuclein and disaggregates preformed fibrils: implications for Parkinson's disease
Fatima Kamal Zaidi;
Fatima Kamal Zaidi
Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
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Shashank Deep
Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
Correspondence: Shashank Deep (sdeep@chemistry.iitd.ac.in)
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Publisher: Portland Press Ltd
Received:
October 16 2019
Revision Received:
January 08 2020
Accepted:
January 15 2020
Accepted Manuscript online:
January 15 2020
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2020
Biochem J (2020) 477 (3): 645–670.
Article history
Received:
October 16 2019
Revision Received:
January 08 2020
Accepted:
January 15 2020
Accepted Manuscript online:
January 15 2020
Citation
Fatima Kamal Zaidi, Shashank Deep; Scutellarin inhibits the uninduced and metal-induced aggregation of α-Synuclein and disaggregates preformed fibrils: implications for Parkinson's disease. Biochem J 14 February 2020; 477 (3): 645–670. doi: https://doi.org/10.1042/BCJ20190705
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