ParkinsonFranceV1, Main, Exploration, bibRecord, 000324

Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein.

Identifieur interne : 000324 ( Main/Exploration ); précédent : 000323; suivant : 000325

Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein.

Auteurs : Coralie Di Scala [France] ; Nouara Yahi [France] ; Sonia Boutemeur [France] ; Alessandra Flores [France] ; Léa Rodriguez [France] ; Henri Chahinian [France] ; Jacques Fantini [France]

Source :

Scientific reports [ 2045-2322 ] ; 2016.

RBID : pubmed:27352802

Abstract

Calcium-permeable pores formed by small oligomers of amyloid proteins are the primary pathologic species in Alzheimer's and Parkinson's diseases. However, the molecular mechanisms underlying the assembly of these toxic oligomers in the plasma membrane of brain cells remain unclear. Here we have analyzed and compared the pore-forming capability of a large panel of amyloid proteins including wild-type, variant and truncated forms, as well as synthetic peptides derived from specific domains of Aβ1-42 and α-synuclein. We show that amyloid pore formation involves two membrane lipids, ganglioside and cholesterol, that physically interact with amyloid proteins through specific structural motifs. Mutation or deletion of these motifs abolished pore formation. Moreover, α-synuclein (Parkinson) and Aβ peptide (Alzheimer) did no longer form Ca(2+)-permeable pores in presence of drugs that target either cholesterol or ganglioside or both membrane lipids. These results indicate that gangliosides and cholesterol cooperate to favor the formation of amyloid pores through a common molecular mechanism that can be jammed at two different steps, suggesting the possibility of a universal therapeutic approach for neurodegenerative diseases. Finally we present the first successful evaluation of such a new therapeutic approach (coined "membrane therapy") targeting amyloid pores formed by Aβ1-42 and α-synuclein.

DOI: 10.1038/srep28781
PubMed: 27352802

Affiliations:

Le document en format XML

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<front><div type="abstract" xml:lang="en">Calcium-permeable pores formed by small oligomers of amyloid proteins are the primary pathologic species in Alzheimer's and Parkinson's diseases. However, the molecular mechanisms underlying the assembly of these toxic oligomers in the plasma membrane of brain cells remain unclear. Here we have analyzed and compared the pore-forming capability of a large panel of amyloid proteins including wild-type, variant and truncated forms, as well as synthetic peptides derived from specific domains of Aβ1-42 and α-synuclein. We show that amyloid pore formation involves two membrane lipids, ganglioside and cholesterol, that physically interact with amyloid proteins through specific structural motifs. Mutation or deletion of these motifs abolished pore formation. Moreover, α-synuclein (Parkinson) and Aβ peptide (Alzheimer) did no longer form Ca(2+)-permeable pores in presence of drugs that target either cholesterol or ganglioside or both membrane lipids. These results indicate that gangliosides and cholesterol cooperate to favor the formation of amyloid pores through a common molecular mechanism that can be jammed at two different steps, suggesting the possibility of a universal therapeutic approach for neurodegenerative diseases. Finally we present the first successful evaluation of such a new therapeutic approach (coined "membrane therapy") targeting amyloid pores formed by Aβ1-42 and α-synuclein.</div>
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La maladie de Parkinson en France (serveur d'exploration)

Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein.

Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein.

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Abstract

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