Inhibition of protein misfolding and aggregation by natural phenolic compounds

Abstract

Protein misfolding and aggregation into fibrillar deposits is a common feature of a large group of degenerative diseases affecting the central nervous system or peripheral organs, termed protein misfolding disorders (PMDs). Despite their established toxic nature, clinical trials aiming to reduce misfolded aggregates have been unsuccessful in treating or curing PMDs. An interesting possibility for disease intervention is the regular intake of natural food or herbal extracts, which contain active molecules that inhibit aggregation or induce the disassembly of misfolded aggregates. Among natural compounds, phenolic molecules are of particular interest, since most have dual activity as amyloid aggregation inhibitors and antioxidants. In this article, we review many phenolic natural compounds which have been reported in diverse model systems to have the potential to delay or prevent the development of various PMDs, including Alzheimer's and Parkinson's diseases, prion diseases, amyotrophic lateral sclerosis, systemic amyloidosis, and type 2 diabetes. The lower toxicity of natural compounds compared to synthetic chemical molecules suggest that they could serve as a good starting point to discover protein misfolding inhibitors that might be useful for the treatment of various incurable diseases.

Islet Amyloid Polypeptide: A Partner in Crime With Aβ in the Pathology of Alzheimer's Disease

“…The pleiotropic action of (poly)phenols toward chronic diseases, particularly diabetes, is well-documented (Bahadoran et al, 2013;Panickar, 2013;Jasmin and Jaitak, 2019;Silveira et al, 2019). Most importantly, (poly)phenols have been linked to the inhibition of aggregation of proteins such as IAPP and Aβ-42 (Pithadia et al, 2016;Sequeira and Poppitt, 2017;Dhouafli et al, 2018). It has been shown that different classes of (poly)phenols may interfere with different steps of the oligomerization process (Ladiwala et al, 2011).…”

Secondary Metabolites from Plants Possessing Inhibitory Properties against Beta-Amyloid Aggregation as Revealed by Thioflavin-T Assay and Correlations with Investigations on Transgenic Mouse Models of Alzheimer’s Disease

“…In the amyloid fibrils, the amino-terminal end of the amyloid-beta peptide is exposed to the interaction with other molecules, while the middle region and the carboxyl-terminal end of the peptide are involved in intramolecular and intermolecular interactions between molecules of Aβ [ 9 ]. Molecules which belong to various classes were analyzed in previous studies as non-covalent binding partners for Aβ peptide: antibodies, peptides, proteins and low molecular weight molecules [ 3 , 4 , 8 , 10 ]. The methods employed most often for comparing aggregation, and particularly amyloid fibril formation using different experimental conditions, are the thioflavin T assay ( Figure 1 ), transmission electron microscopy, atomic force microscopy, and scanning electron microscopy.…”

Simultaneous Occurrence of Bioactive Compounds (Melatonin, Protocatechuic Acid and Hydroxytyrosol) Increases Their Neuroprotective Effects Against Alpha-Synuclein-Induced Proteotoxicity

“…The mechanism of action remains unclear and seems to be through the modulation of multiple pathways. A proposed mechanism is through the modulation of toxic oligomer formation by binding and stabilizing unfolded species of α-Syn reducing fibrillation and redirecting the aggregation pathway to form off-pathway, amorphous non-toxic aggregates, blocking seeding and further conformational changes that may result in aggregation and cytotoxicity [81,82].…”