title: Broad neutralization of calcium-permeable amyloid pore channels with a chimeric Alzheimer/Parkinson peptide targeting brain gangliosides.
abstract: Growing evidence supports a role for brain gangliosides in the pathogenesis of neurodegenerative diseases including Alzheimer's and Parkinson's. Recently we deciphered the ganglioside-recognition code controlling specific ganglioside binding to Alzheimer's β-amyloid (Aβ1-42) peptide and Parkinson's disease-associated protein α-synuclein. Cracking this code allowed us to engineer a short chimeric Aβ/α-synuclein peptide that recognizes all brain gangliosides. Here we show that ganglioside-deprived neural cells do no longer sustain the formation of zinc-sensitive amyloid pore channels induced by either Aβ1-42 or α-synuclein, as assessed by single-cell Ca(2+) fluorescence microscopy. Thus, amyloid channel formation, now considered a key step in neurodegeneration, is a ganglioside-dependent process. Nanomolar concentrations of chimeric peptide competitively inhibited amyloid pore formation induced by Aβ1-42 or α-synuclein in cultured neural cells. Moreover, this peptide abrogated the intracellular calcium increases induced by Parkinson's-associated mutant forms of α-synuclein (A30P, E46K and A53T). The chimeric peptide also prevented the deleterious effects of Aβ1-42 on synaptic vesicle trafficking and decreased the Aβ1-42-induced impairment of spontaneous activity in rat hippocampal slices. Taken together, these data show that the chimeric peptide has broad anti-amyloid pore activity, suggesting that a common therapeutic strategy based on the prevention of amyloid-ganglioside interactions is a reachable goal for both Alzheimer's and Parkinson's diseases.
authors.affiliation: Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, Marseille, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Di Scala
authors.affiliation: Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, Marseille, France.
authors.forename: Nouara
authors.initials: N
authors.lastname: Yahi
authors.affiliation: Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, Marseille, France.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Flores
authors.affiliation: Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, Marseille, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Boutemeur
authors.affiliation: INSERM, INMED, Parc Scientifique de Luminy, 13009 Marseille, France.
authors.forename: Nazim
authors.initials: N
authors.lastname: Kourdougli
authors.affiliation: Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, Marseille, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Chahinian
authors.affiliation: Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, Marseille, France. Electronic address: jacques.fantini@univ-amu.fr.
authors.forename: Jacques
authors.initials: J
authors.lastname: Fantini
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D005732:Gangliosides / Q000378:metabolism*; D006801:Humans; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D010539:Permeability; D017208:Rats, Wistar; D015032:Zinc / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D005732:Gangliosides; D010446:Peptide Fragments; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); D015032:Zinc; D002118:Calcium
keywords: Alzheimer; Amyloid pore; Calcium; Ganglioside; Ion channel; Parkinson; α-Synuclein; β-amyloid peptide