Polyphenolic compounds are novel protective agents against lipid membrane damage by α-synuclein aggregates in vitro
| Autor: | Tobias Högen, Neville Vassallo, Frits Kamp, Charles Scerri, Johanna Neuner, Mario Caruana, Armin Giese, Felix Schmidt |
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| Rok vydání: | 2012 |
| Předmět: |
Cell Membrane Permeability
Parkinson's disease Biophysics Peptide In Vitro Techniques Biochemistry chemistry.chemical_compound Membrane Lipids Structure-Activity Relationship Lipid bilayer Alpha-synuclein chemistry.chemical_classification α-Synuclein Liposome Vesicle Polyphenols Cell Biology Membrane permeabilisation Nordihydroguaiaretic acid Kinetics Lipid vesicle Spectrometry Fluorescence chemistry Oligomers Liposomes Gramicidin Synuclein alpha-Synuclein |
| Zdroj: | Biochimica et biophysica acta. 1818(11) |
| ISSN: | 0006-3002 |
| Popis: | Cumulative evidence now suggests that the abnormal aggregation of the protein α-synuclein (αS) is a critical factor in triggering neurodegeneration in Parkinson's disease (PD). In particular, a fundamental pathogenetic mechanism appears to involve targeting of neuronal membranes by soluble oligomeric intermediates of αS, leading to their disruption or permeabilisation. Therefore, a model assay was developed in which fluorophore-loaded unilamellar vesicles were permeabilised by soluble oligomers, the latter formed by aggregation of human recombinant αS protein. The αS oligomers induced an impairment of membrane integrity similar to that of the pore-forming bacterial peptide gramicidin. The lipid vesicle permeabilisation assay was then utilised to screen 11 natural polyphenolic compounds, 8 synthetic N′-benzylidene-benzohydrazide compounds and black tea extract for protection against membrane damage by wild-type and mutant (A30P, A53T) synuclein aggregates. A select group of potent inhibitory compounds included apigenin, baicalein, morin, nordihydroguaiaretic acid, and black tea extract. Structure–activity analysis further suggests that a 5,7-dihydroxy-chromen-4-one moiety appears to be favourable for the inhibition reaction. In conclusion, we have identified a group of polyphenols that can effectively hinder membrane damage by αS aggregates. These may serve as a viable source of lead compounds for the development and design of novel therapeutic agents in PD. |
| Databáze: | OpenAIRE |
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