Triphala inhibits alpha-synuclein fibrillization and their interaction study by NMR provides insights into the self-association of the protein |
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Authors: | Mandar Bopardikar Anusri Bhattacharya Veera Mohana Rao Kakita Kavitha Rachineni Lalit C Borde Sinjan Choudhary Sri Rama Koti Ainavarapu Ramakrishna V Hosur |
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Institution: | Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005 India.; UM-DAE Centre for Excellence in Basic Sciences, University of Mumbai, Kalina Campus, Santacruz, Mumbai 400098 India ; Department of Biological Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005 India |
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Abstract: | The process of assembly and accumulation of the intrinsically disordered protein (IDP), alpha-synuclein (αSyn) into amyloid fibrils is a pathogenic process leading to several neurodegenerative disorders such as Parkinson''s disease, multiple system atrophy and others. Although several molecules are known to inhibit αSyn fibrillization, the mechanism of inhibition is just beginning to emerge. Here, we report the inhibition of fibrillization of αSyn by Triphala, a herbal preparation in the traditional Indian medical system of Ayurveda. Triphala was found to be a rich source of polyphenols which are known to act as amyloid inhibitors. ThT fluorescence and TEM studies showed that Triphala inhibited the fibrillization of αSyn. However, it was observed that Triphala does not disaggregate preformed αSyn fibrils. Further, native-PAGE showed that Triphala reduces the propensity of αSyn to oligomerize during the lag phase of fibrillization. Our NMR results showed that certain stretches of residues in the N-terminal and NAC regions of αSyn play an anchor role in the self-association process of the protein, thereby providing mechanistic insights into the early events during αSyn fibrillization.Triphala inhibits αSyn self-association by interacting with anchoring regions which are responsible for αSyn oligomerization. |
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