Genipin prevents alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage

Abstract

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 α-synuclein (αSyn) 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 αSyn 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 overexpression of αSyn in a Drosophila melanogaster model of PD. These findings widens the possibility for the exploitation of genipin for PD therapeutics.

Resveratrol inhibits calcium oxalate crystal growth, reduces adhesion to renal cells and induces crystal internalization into the cells, but promotes crystal aggregation

“…Likewise, other phenolic compounds, such as quercetin, can also enhance the phagocytic activity of leukocytes ( Boonlaos et al, 2021 ). Additionally, genipin (another type of plant-derived bioactive compound) can aggravate the endocytic activity of yeast cells to prevent α-synuclein-induced cytotoxicity ( Rosado-Ramos et al, 2023 ). Therefore, resveratrol may activate macropinocytosis or endocytosis of renal epithelial cells, thereby promoting crystal internalization to prompt the crystals for degradation by endolysosomes ( Fig.…”

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

“…These molecules are known to alleviate ER stress in neurons by decreasing α-syn burden and switching UPR activation towards cytoprotective response, which mainly involves upregulation of the Nrf2 pathway [ 196 , 197 ]. The anti-aggregation effect of these compounds is induced by (i) decrease in α-syn expression (resveratrol), (ii) stabilization of α-syn molecules (baicalein, GA, NDGA, EGCG, ginsenoside Rb1), (iii) inhibition of oligomerization (curcumin, baicalein, EA), (iv) disruption of lipid–protein interaction (EA, EGCG, squalamine, trodusquemine), (v) destabilization of assemblies (curcumin, baicalein, EA, GA, EGCG, squalamine, trodusquemine), (vi) inhibition of fibrillization (curcumin, baicalein, cuminaldehyde, delphinidin, GA and EGCG), (vii) formation of non-toxic off-pathway aggregates (ferulic acid, EGCG), (viii) increase in α-syn clearance (celastrol, resveratrol, genipin, isorhynchophylline) [ 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 ]. Apart from α-syn, curcumin was shown to inhibit Aβ aggregation, and EGCG was reported to disrupt aggregation of a least 14 other amyloidogenic proteins [ 217 , 218 ]; these findings are important in the view of cross-seeding effect.…”