Brazilin Removes Toxic alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium

Nahass, George R.; Sun, Yun; Xu, Yong; Batchelor, Mark; Reilly, M.; Benilova, Iryna; Kedia, Niraja; Spehar, Kevin; Sobott, Frank; Sessions, Richard B.; Caughey, Byron; Radford, Sheena E.; Jat, Parmjit; Collinge, John; Bieschke, Jan

doi:10.1101/2020.09.29.318220

Cited by 2 publications

(3 citation statements)

References 71 publications

(151 reference statements)

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“…The amyloid β‐sheet structure can be specifically recognized by Thioflavin T (ThT) [51] . We then monitored the kinetics of α‐Syn amyloid aggregation under phase separation using ThT fluorescence [15,52] . A time‐dependent increase of ThT fluorescence intensity indicated the formation of α‐Syn amyloid aggregates (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Myricetin Inhibits α‐Synuclein Amyloid Aggregation by Delaying the Liquid‐to‐Solid Phase Transition

Chen

et al. 2022

ChemBioChem

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The aggregation of α-synuclein (α-Syn) is a critical pathological hallmark of Parkinson's disease (PD). Prevention of α-Syn aggregation has become a key strategy for treating PD. Recent studies have suggested that α-Syn undergoes liquid-liquid phase separation (LLPS) to facilitate nucleation and amyloid formation. Here, we examined the modulation of α-Syn aggregation by myricetin, a polyhydroxyflavonol compound, under the conditions of LLPS. Unexpectedly, neither the initial morphology nor the phase-separated fraction of α-Syn was altered by myricetin. However, the dynamics of α-Syn con-densates decreased upon myricetin binding. Further studies showed that myricetin dose-dependently inhibits amyloid aggregation in the condensates by delaying the liquid-to-solid phase transition. In addition, myricetin could disassemble the preformed α-Syn amyloid aggregates matured from the condensates. Together, our study shows that myricetin inhibits α-Syn amyloid aggregation in the condensates by retarding the liquid-to-solid phase transition and reveals that α-Syn phase transition can be targeted to inhibit amyloid aggregation. www.chembiochem.org

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Section: Resultsmentioning

confidence: 99%

Myricetin Inhibits α‐Synuclein Amyloid Aggregation by Delaying the Liquid‐to‐Solid Phase Transition

Chen

et al. 2022

ChemBioChem

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“…The compound has multiple pharmacological activities, including cardioand neuroprotective effects, preventing myocardial ischemia-reperfusion injury 17 and inhibiting fibrillogenesis of α-synuclein in brain. 18,19 The compound may be useful for treating neurodegenerative disorders, such as Parkinson's disease. 20 Brazilin also displays antidepressant-and anxiolytic-like effects, 21 antimicrobial activity, 22 and anticancer properties.…”

Section: Introductionmentioning

confidence: 99%

“…Brazilin is a tetracyclic phenolic compound (natural red number 24) derived from red cedarwood trees in Brazil, Caesalpinia echinata Lam., known as Brazil wood. The compound has multiple pharmacological activities, including cardio‐ and neuroprotective effects, preventing myocardial ischemia–reperfusion injury 17 and inhibiting fibrillogenesis of α‐synuclein in brain 18,19 . The compound may be useful for treating neurodegenerative disorders, such as Parkinson's disease 20 .…”

Section: Introductionmentioning

confidence: 99%

Molecular docking of brazilin and its analogs to barrier‐to‐autointegration factor 1 (BAF1)

Soeiro

Vergoten

Bailly

2022

Annals of the New York Academy of Sciences

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The tetracyclic phenolic compound brazilin, derived from the wood of Caesalpinia sappan, has been shown to bind to the chromatin protein BAF1 (barrier-to-autointegration factor 1), a protein essential to maintain integrity of the nuclear envelope in cells. BAF1 plays a role in cancer development. Using molecular docking, we have located the binding site for brazilin on the surface of the BAF1 monomer and compared its binding to that of four analogs. The oxidized product brazilein ( E = −57.7 kcal/mol) exhibits a higher affinity for BAF1 compared to the reduced form brazilin ( E = −38.2 kcal/mol). Incorporation of a 4-hydroxyl substituent on the indenochromene unit affords hematoxylin and hematein. In silico analysis predicts that the oxidized form hematein ( E = −66.2 kcal/mol) displays a higher affinity for BAF1 than the reduced form hematoxylin ( E = −42.2 kcal/mol). In contrast, the atypical bis-lactone product brazilide A cannot form good complexes with BAF1. The analysis points to the formation of more stable BAF1 complexes with the oxidized molecules compared to the reduced ones, but the position of the binding site on the protein cavity is different for brazilin/hematoxylin compared to brazilein/hematein. Our study may be useful to guide the design of BAF1 ligands.

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Brazilin Removes Toxic alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium

Cited by 2 publications

References 71 publications

Myricetin Inhibits α‐Synuclein Amyloid Aggregation by Delaying the Liquid‐to‐Solid Phase Transition

Myricetin Inhibits α‐Synuclein Amyloid Aggregation by Delaying the Liquid‐to‐Solid Phase Transition

Molecular docking of brazilin and its analogs to barrier‐to‐autointegration factor 1 (BAF1)

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