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

Rita Rosado-Ramos, Gonçalo M. Poças, Daniela Marques, Alexandre Foito, David M. Sevillano, Mafalda Lopes-da-Silva, Luís G. Gonçalves, Regina Menezes, Marcel Ottens, Derek Stewart, Alain Ibáñez de Opakua, Markus Zweckstetter, Miguel C. Seabra, César S. Mendes, Tiago Fleming Outeiro, Pedro M. Domingos and Cláudia N. Santos ()
Additional contact information
Rita Rosado-Ramos: iBET, Instituto de Biologia Experimental e Tecnológica
Gonçalo M. Poças: Universidade Nova de Lisboa (ITQB NOVA)
Daniela Marques: Universidade Nova de Lisboa
Alexandre Foito: Environmental and Biochemical Sciences, The James Hutton Institute
David M. Sevillano: Delft University of Technology
Mafalda Lopes-da-Silva: Universidade Nova de Lisboa
Luís G. Gonçalves: Universidade Nova de Lisboa (ITQB NOVA)
Regina Menezes: iBET, Instituto de Biologia Experimental e Tecnológica
Marcel Ottens: Delft University of Technology
Derek Stewart: Environmental and Biochemical Sciences, The James Hutton Institute
Alain Ibáñez de Opakua: German Center for Neurodegenerative Diseases (DZNE)
Markus Zweckstetter: German Center for Neurodegenerative Diseases (DZNE)
Miguel C. Seabra: Universidade Nova de Lisboa
César S. Mendes: Universidade Nova de Lisboa
Tiago Fleming Outeiro: German Center for Neurodegenerative Diseases (DZNE)
Pedro M. Domingos: Universidade Nova de Lisboa (ITQB NOVA)
Cláudia N. Santos: iBET, Instituto de Biologia Experimental e Tecnológica

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37561-2

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