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

Abstract

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

Sideritis scardica Extracts Demonstrate Neuroprotective Activity against Aβ25–35 Toxicity

“…Nevertheless, the more polar extracts, such as the methanolic and aqueous extracts, are the strongest in terms of neuroprotectivity, as also indicated by previous findings [36][37][38][39]. The presence of known neuroprotective SS compounds (Tables 1 and 2), such as luteolin, apigenin, ferulic acid, chlorogenic acid, caffeic acid, ellagic acid, myricetin, quercetin, protocatechuic acid, gallic acid, vanillic acid, syringic acid, p-coumaric acid, kaempferol, verbascoside, and forsythoside A, likely confers Aβ 25-35 anti-neurotoxicity to the four neuroprotective fractions presented here [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98]. Notably, ellagic acid and myricetin-3-O-galactoside are enriched in these four fractions, proportionally to their neuroprotective potential.…”

Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease

“…It is worth mentioning that some polyphenols, such as myricetin and curcumin, have been recently described to inhibit α-Syn liquid-to-solid transition in LLPS condensates. Adding these polyphenols to the condensates did not impact their morphology, but they increased the protein solubility, preventing amyloid transition and disentangling the preformed aggregates [ 253 , 254 ]. Structure–Activity Relationship (SAR) analysis of multiple phenolic variants with inhibitory activity revealed that the phenyl group alone does not prevent fibril formation [ 255 ].…”

Light, Water, and Melatonin: The Synergistic Regulation of Phase Separation in Dementia

“…The documentation of the conformational evolution of αSyn phase transitions has been successfully captured by solution and solid-state magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopies [ 51 ], and the study and analysis of the material components as well as intermolecular interactions of protein molecules within αSyn condensates during phase separations were performed employing fluorescence recovery after photobleaching (FRAP) and Förster resonance energy transfer (FRET) techniques [ 80 ]. Since phase separation is an early event in αSyn aggregation, modulating phase separation and/or interfering with liquid-to-solid phase transitions during αSyn amyloid phase transitions become attractive molecular targets [ 81 ].…”