title: Extracts from two ubiquitous Mediterranean plants ameliorate cellular and animal models of neurodegenerative proteinopathies.
abstract: A signature feature of age-related neurodegenerative proteinopathies is the misfolding and aggregation of proteins, typically amyloid-β (Aβ) in Alzheimer's disease (AD) and α-synuclein (α-syn) in Parkinson's disease (PD), into soluble oligomeric structures that are highly neurotoxic. Cellular and animal models that faithfully replicate the hallmark features of these disorders are being increasing exploited to identify disease-modifying compounds. Natural compounds have been identified as a useful source of bioactive molecules with promising neuroprotective capabilities. In the present report, we investigated whether extracts derived from two ubiquitous Mediterranean plants namely, the prickly pear Opuntia ficus-indica (EOFI) and the brown alga Padina pavonica (EPP) alleviate neurodegenerative phenotypes in yeast (Saccharomyces cerevisiae) and fly (Drosophila melanogaster) models of AD and PD. Pre-treatment with EPP or EOFI in the culture medium significantly improved the viability of yeast expressing the Arctic Aβ42 (E22G) mutant. Supplementing food with EOFI or EPP dramatically ameliorated lifespan and behavioural signs of flies with brain-specific expression of wild-type Aβ42 (model of late-onset AD) or the Arctic Aβ42 variant (model of early-onset AD). Additionally, we show that either extract prolonged the survival of a PD fly model based on transgenic expression of the human α-syn A53T mutant. Taken together, our findings suggest that the plant-derived extracts interfere with shared mechanisms of neurodegeneration in AD and PD. This notion is strengthened by evidence demonstrating that EOFI and to a greater extent EPP, while strongly inhibiting the fibrillogenesis of both Aβ42 and α-syn, accumulate remodelled oligomeric aggregates that are less effective at disrupting lipid membrane integrity. Our work therefore opens new avenues for developing therapeutic applications of these natural plant extracts in the treatment of amyloidogenic neurodegenerative disorders.
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Institute de Chimie et de Biologie des Membranes et des Nano-Objets, CNRS-UMR5248, Université Bordeaux, Pessac, France; Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta, Msida, Malta.
authors.forename: Michelle
authors.initials: M
authors.lastname: Briffa
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta, Msida, Malta.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ghio
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.
authors.forename: Johanna
authors.initials: J
authors.lastname: Neuner
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Gauci
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta, Msida, Malta.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cacciottolo
authors.affiliation: Institute de Chimie et de Biologie des Membranes et des Nano-Objets, CNRS-UMR5248, Université Bordeaux, Pessac, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Marchal
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta, Msida, Malta.
authors.forename: Mario
authors.initials: M
authors.lastname: Caruana
authors.affiliation: Institute de Chimie et de Biologie des Membranes et des Nano-Objets, CNRS-UMR5248, Université Bordeaux, Pessac, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Cullin
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta, Msida, Malta.
authors.forename: Neville
authors.initials: N
authors.lastname: Vassallo
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta, Msida, Malta. Electronic address: ruben.cauchi@um.edu.mt.
authors.forename: Ruben J
authors.initials: RJ
authors.lastname: Cauchi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004331:Drosophila melanogaster; D006801:Humans; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D029747:Opuntia / Q000737:chemistry*; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D000459:Phaeophyceae / Q000737:chemistry*; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000502:physiology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010936:Plant Extracts; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42)
keywords: Amyloid-β (Aβ) peptide; Model organisms; Neurodegenerative proteinopathies; Opuntia ficus-indica extract; Padina pavonica extract; α-Synuclein (α-syn) protein