alpha-synuclein and myricetin

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 condensates 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.

Topics: alpha-Synuclein; Amyloid; Amyloidogenic Proteins; Amyloidosis; Flavonoids; Humans; Parkinson Disease

Major neurodegenerative disorders are characterized by the formation of misfolded proteins aggregates inside or outside the neuronal cells. Previous studies suggest that aberrant proteins aggregates play a critical role in protein homeostasis imbalance and failure of protein quality control (PQC) mechanism, leading to disease conditions. However, we still do not understand the precise mechanisms of PQC failure and cellular dysfunctions associated with neurodegenerative diseases caused by the accumulation of protein aggregates. Here, we show that Myricetin, a flavonoid, can eliminate various abnormal proteins from the cellular environment via modulating endogenous levels of Hsp70 chaperone and quality control (QC)-E3 ubiquitin ligase E6-AP. We have observed that Myricetin treatment suppresses the aggregation of different aberrant proteins. Myricetin also enhances the elimination of various toxic neurodegenerative diseases associated proteins from the cells, which could be reversed by the addition of putative proteasome inhibitor (MG132). Remarkably, Myricetin can also stabilize E6-AP and reduce the misfolded proteins inclusions, which further alleviates cytotoxicity. Taken together these findings suggested that new mechanistic and therapeutic insights based on small molecules mediated regulation of disturbed protein quality control mechanism, which may result in the maintenance of the state of proteostasis.

Topics: A549 Cells; alpha-Synuclein; Enzyme Stability; Flavonoids; Humans; Inclusion Bodies; Luciferases; Models, Biological; Mutant Proteins; Nerve Degeneration; Peptides; Polyphenols; Proteasome Endopeptidase Complex; Protein Aggregates; Protein Folding; Proteolysis; Solubility; Stress, Physiological; Superoxide Dismutase; Ubiquitin-Protein Ligases; Up-Regulation

Lewy bodies, mainly composed of α-synuclein (αS), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that green tea consumption or habitual intake of phenolic compounds reduced Parkinson's disease risk. We previously reported that phenolic compounds inhibited αS fibrillation and destabilized preformed αS fibrils. Cumulative evidence suggests that low-order αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (RA), nordihydroguaiaretic acid, and ferulic acid) on αS oligomerization. Using methods such as photo-induced cross-linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and RA inhibited αS oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N-terminal region of αS, whereas direct binding of RA to monomeric αS was not detected. Electrophysiological assays for long-term potentiation in mouse hippocampal slices revealed that Myr and RA ameliorated αS synaptic toxicity by inhibition of αS oligomerization. These results suggest that Myr and RA prevent the αS aggregation process, reducing the neurotoxicity of αS oligomers. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds on α-synuclein (αS) oligomerization. Phenolic compounds, especially Myricetin (Myr) and Rosmarinic acid (RA), inhibited αS oligomerization and secondary structure conversion. Myr and RA ameliorated αS synaptic toxicity on the experiment of long-term potentiation. Our results suggest that Myr and RA prevent αS aggregation process and reduce the neurotoxicity of αS oligomers. Phenolic compounds are good candidates of disease modifying drugs for α-synucleinopathies.

Topics: alpha-Synuclein; Amyloid; Animals; Antioxidants; Cinnamates; Circular Dichroism; Coumaric Acids; Curcumin; Depsides; Drug Evaluation, Preclinical; Flavonoids; Hippocampus; Long-Term Potentiation; Masoprocol; Mice; Microscopy, Atomic Force; Models, Molecular; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Phenols; Polymerization; Protein Structure, Secondary; Rosmarinic Acid