Small Molecule Fisetin Modulates Alpha-Synuclein Aggregation

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 11; p. 3353
• Main Authors: Rosado-Ramos, Rita, Godinho-Pereira, Joana, Marques, Daniela, Figueira, Inês, Fleming Outeiro, Tiago, Menezes, Regina, Nunes Dos Santos, Cláudia
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 02-06-2021; MDPI
• Subjects: alpha-Synuclein - metabolism; Apoptosis; Butyl hydroperoxide; Butyrates - adverse effects; Cell differentiation; Cell Line; Dopamine; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine receptors; Dopamine transporter; Enzymes; flavonoid; Flavonoids; Flavonols - pharmacology; Humans; Inclusions; Inflammation; Kinases; Localization; Models, Biological; MPP; Neurodegeneration; Neuroprotection; Neurotoxicity; Oxidative Stress; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson's disease; Pathology; Phenolic compounds; Phenols; Physiology; Piperidines - adverse effects; Protein Aggregates - drug effects; Proteins; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - metabolism; Synuclein; tert-Butylhydroperoxide - metabolism; Toxicity; Tumor necrosis factor-TNF; Yeasts; α-synuclein; Parkinson’s Disease; dopamine transporter; flavonoid; α-synuclein
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26113353

Phenolic compounds are thought to be important to prevent neurodegenerative diseases (ND). Parkinson's Disease (PD) is a neurodegenerative disorder known for its typical motor features, the deposition of α-synuclein (αsyn)-positive inclusions in the brain, and for concomitant cellular pathologies that include oxidative stress and neuroinflammation. Neuroprotective activity of fisetin, a dietary flavonoid, was evaluated against main hallmarks of PD in relevant cellular models. At physiologically relevant concentrations, fisetin protected SH-SY5Y cells against oxidative stress overtaken by
-butyl hydroperoxide (
-BHP) and against methyl-4-phenylpyridinuim (MPP
)-induced toxicity in dopaminergic neurons, the differentiated Lund human Mesencephalic (LUHMES) cells. In this cellular model, fisetin promotes the increase of the levels of dopamine transporter. Remarkably, fisetin reduced the percentage of cells containing αsyn inclusions as well as their size and subcellular localization in a yeast model of αsyn aggregation. Overall, our data show that fisetin exerts modulatory activities toward common cellular pathologies present in PD; remarkably, it modulates αsyn aggregation, supporting the idea that diets rich in this compound may prove beneficial.