The small iridoid compound genipin prevents alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage

Parkinson's Disease (PD) is a common neurodegenerative disorder affecting millions of people worldwide for which there are only symptomatic therapies. Small molecules able to target key pathological processes in PD have emerged as interesting options for modifying disease progression. We have previously shown that a (poly)phenol-enriched fraction (PEF) of Corema album L. leaf extract modulates central events in PD pathogenesis, namely a-synuclein (aSyn) toxicity, aggregation and clearance. PEF was now subjected to a bio-guided fractionation with the aim of identifying the critical bioactive compound. We identified genipin, an iridoid, which relieves aSyn toxicity and aggregation. Furthermore, genipin promotes metabolic alterations and modulates lipid storage and endocytosis. Importantly, genipin was able to prevent the motor deficits caused by the expression of aSyn-GFP in a Drosophila melanogaster model of PD. These findings open new avenues for the exploitation of genipin for PD therapeutics. Overall design: Yeast cells, either controls or disease model were incubated with genipin, a protective compound, and the transcriptomics were assessed.