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Broad neutralization of calcium-permeable amyloid pore channels with a ă chimeric Alzheimer/Parkinson peptide targeting brain gangliosides

Abstract : Growing evidence supports a role for brain gangliosides in the ă pathogenesis of neurodegenerative diseases including Alzheimer's and ă Parkinson's. Recently we deciphered the ganglioside-recognition code ă controlling specific ganglioside binding to Alzheimer's beta-amyloid (A ă beta 1-42) peptide and Parkinson's disease-associated protein ă alpha-synuclein. Cracking this code allowed us to engineer a short ă chimeric A beta/alpha-synuclein peptide that recognizes all brain ă gangliosides. Here we show that ganglioside-deprived neural cells do no ă longer sustain the formation of zinc-sensitive amyloid pore channels ă induced by either A beta 1-42 or alpha-synuclein, as assessed by ă single-cell Ca2+ fluorescence microscopy. Thus, amyloid channel ă formation, now considered a key step in neurodegeneration, is a ă ganglioside-dependent process. Nanomolar concentrations of chimeric ă peptide competitively inhibited amyloid pore formation induced by A beta ă 1-42 or alpha-synudein in cultured neural cells. Moreover, this peptide ă abrogated the intracellular calcium increases induced by ă Parkinson's-associated mutant forms of alpha-synuclein (A30P, E46K and ă A53T). The chimeric peptide also prevented the deleterious effects of A ă beta 1-42 on synaptic vesicle trafficking and decreased the A beta ă 1-42-induced impairment of spontaneous activity in rat hippocampal ă slices. Taken together, these data show that the chimeric peptide has ă broad anti-amyloid pore activity, suggesting that a common therapeutic ă strategy based on the prevention of amyloid-ganglioside interactions is ă a reachable goal for both Alzheimer's and Parkinson's diseases. (C) 2015 ă Elsevier B.V. All rights reserved.
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Contributor : Jérôme Trouslard Connect in order to contact the contributor
Submitted on : Monday, February 20, 2017 - 2:07:33 PM
Last modification on : Wednesday, November 3, 2021 - 7:58:45 AM

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Coralie Di Scala, Nouara Yahi, Alessandra Flores, Ă Sonia Boutemeur, Nazim Kourdougli, et al.. Broad neutralization of calcium-permeable amyloid pore channels with a ă chimeric Alzheimer/Parkinson peptide targeting brain gangliosides. Biochimica et Biophysica Acta - Molecular Basis of Disease, Elsevier, 2016, 1862 (2), pp.213-222. ⟨10.1016/j.bbadis.2015.11.012⟩. ⟨hal-01471935⟩



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