Oleuropein aglycone stabilizes the monomeric α-synuclein and favours the growth of non-toxic aggregates

Abstract

α-synuclein plays a key role in the pathogenesis of Parkinson’s disease (PD); its deposits are found as amyloid fibrils in Lewy bodies and Lewy neurites, the histopathological hallmarks of PD. Amyloid fibrillation is a progressive polymerization path starting from peptide/protein misfolding and proceeding through the transient growth of oligomeric intermediates widely considered as the most toxic species. Consequently, a promising approach of intervention against PD might be preventing α-synuclein build-up, misfolding and aggregation. A possible strategy involves the use of small molecules able to slow down the aggregation process or to alter oligomer conformation favouring the growth of non-pathogenic species. Here, we show that oleuropein aglycone (OleA), the main olive oil polyphenol, exhibits anti-amyloidogenic power in vitro by interacting with, and stabilizing, α-synuclein monomers thus hampering the growth of on-pathway oligomers and favouring the growth of stable and harmless aggregates with no tendency to evolve into other cytotoxic amyloids. We investigated the molecular basis of such interference by both biophysical techniques and limited proteolysis; aggregate morphology was monitored by electron microscopy. We also found that OleA reduces the cytotoxicity of α-synuclein aggregates by hindering their binding to cell membrane components and preventing the resulting oxidative damage to cells.

Oleuropein, a Bioactive Compound from Olea europaea L., as a Potential Preventive and Therapeutic Agent in Non-Communicable Diseases

“…OleA has been found to decrease toxic oligomers formation in vitro experiments of Aβ peptide and α-synuclein amyloid aggregation, as well as to promote fibril and plaque disaggregation [122][123][124]. These actions reflect its beneficial effects against amyloid toxicity to cultured cells [122] and in transgenic model organisms [125,126].…”

Polyphenols from Food and Natural Products: Neuroprotection and Safety

“…Further examples of polyphenols pinpointed as promising molecules in the prevention and treatment of neurodegenerative diseases can be found in the literature [21,[47][48][49][50][51]. One of the most relevant examples is resveratrol, shown to have neuroprotective properties by decreasing microglia-induced neuroinflammation, protecting the brain against hypoxic-ischemic damage and ameliorating cognitive function in the Alzheimer's disease model [38][39][40]52].…”

Healthspan Maintenance and Prevention of Parkinson’s-like Phenotypes with Hydroxytyrosol and Oleuropein Aglycone in C. elegans

“…In the present paper, we focus on health effects of hydroxytyrosol (HT; Figure 1B) and oleuropein aglycone (OLE; Figure 1A) as neuroprotective agents against PD in the light of recent studies indicating that OLE and HT can be beneficial against PD by stabilizing the monomeric state of α-synuclein, thus, favouring the growth of aggregates devoid of toxicity [36,37]. Furthermore, previous studies have shown that these molecules are strongly protective against neurodegeneration in different transgenic models of Aβ deposition [38][39][40].…”