Polyphenol honokiol and flavone 2′,3′,4′-trihydroxyflavone differentially interact with α-synuclein at distinct phases of aggregation
Date
2020
Authors
Jovcevski, B.
Das, S.
Smid, S.
Pukala, T.L.
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Journal article
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ACS Chemical Neuroscience, 2020; 11(24):4469-4477
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Blagojce Jovcevski, Sukanya Das, Scott Smid, and Tara Louise Pukala
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Abstract
The association between protein aggregation and neurodegenerative diseases such as Parkinson’s disease continues to be well interrogated but poorly elucidated at a mechanistic level. Nevertheless, the formation of amyloid fibrils from the destabilization and misfolding of native proteins is a molecular hallmark of disease. Consequently, there is ongoing demand for the identification and development of small molecules which prevent fibril formation. This study comprehensively assesses the inhibitory properties of two small molecules, the lignan polyphenol honokiol and the flavonoid 2′,3′,4′-trihydroxyflavone, in preventing α-synuclein fibrilization. The data shows that honokiol does not prevent α-synuclein fibril elongation, while 2′,3′,4′-trihydroxyflavone is effective at inhibiting fibril elongation and induces oligomer formation (for both wild-type α-synuclein and the disease-associated A53T mutation). Moreover, the exposed hydrophobicity of α-synuclein fibrils is reduced in the presence of 2′,3′,4′-trihydroxyflavone, whereas the addition of honokiol did not reduce the hydrophobicity of fibrils. In addition, ion mobility–mass spectrometry revealed that the conformation of α-synuclein wild-type and A53T monomers after disassembly is restored to a nonaggregation-prone state upon 2′,3′,4′-trihydroxyflavone treatment. Collectively, this study shows that the mechanisms by which these polyphenols and flavonoids prevent fibril formation are distinct by their interactions at various phases of the fibril-forming pathway. Furthermore, this study highlights how thorough biophysical interrogation of the interaction is required for understanding the ability of inhibitors to prevent protein aggregation associated with disease.
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© 2020 American Chemical Society