Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein.
Identifieur interne : 000127 ( PubMed/Corpus ); précédent : 000126; suivant : 000128Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein.
Auteurs : Coralie Di Scala ; Nouara Yahi ; Sonia Boutemeur ; Alessandra Flores ; Léa Rodriguez ; Henri Chahinian ; Jacques FantiniSource :
- Scientific reports [ 2045-2322 ] ; 2016.
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
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France.</nlm:affiliation></affiliation></author><author><name sortKey="Flores, Alessandra" sort="Flores, Alessandra" uniqKey="Flores A" first="Alessandra" last="Flores">Alessandra Flores</name><affiliation><nlm:affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</nlm:affiliation></affiliation></author><author><name sortKey="Rodriguez, Lea" sort="Rodriguez, Lea" uniqKey="Rodriguez L" first="Léa" last="Rodriguez">Léa Rodriguez</name><affiliation><nlm:affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</nlm:affiliation></affiliation></author><author><name sortKey="Chahinian, Henri" sort="Chahinian, Henri" uniqKey="Chahinian H" first="Henri" last="Chahinian">Henri Chahinian</name><affiliation><nlm:affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</nlm:affiliation></affiliation></author><author><name sortKey="Fantini, Jacques" sort="Fantini, Jacques" uniqKey="Fantini J" first="Jacques" last="Fantini">Jacques Fantini</name><affiliation><nlm:affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27352802</idno><idno type="pmid">27352802</idno><idno type="doi">10.1038/srep28781</idno><idno type="wicri:Area/PubMed/Corpus">000127</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000127</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein.</title><author><name sortKey="Di Scala, Coralie" sort="Di Scala, Coralie" uniqKey="Di Scala C" first="Coralie" last="Di Scala">Coralie Di Scala</name><affiliation><nlm:affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</nlm:affiliation></affiliation></author><author><name sortKey="Yahi, Nouara" sort="Yahi, Nouara" uniqKey="Yahi N" first="Nouara" last="Yahi">Nouara Yahi</name><affiliation><nlm:affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</nlm:affiliation></affiliation></author><author><name sortKey="Boutemeur, Sonia" sort="Boutemeur, Sonia" uniqKey="Boutemeur S" first="Sonia" last="Boutemeur">Sonia Boutemeur</name><affiliation><nlm:affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</nlm:affiliation></affiliation></author><author><name sortKey="Flores, Alessandra" sort="Flores, Alessandra" uniqKey="Flores A" first="Alessandra" last="Flores">Alessandra Flores</name><affiliation><nlm:affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</nlm:affiliation></affiliation></author><author><name sortKey="Rodriguez, Lea" sort="Rodriguez, Lea" uniqKey="Rodriguez L" first="Léa" last="Rodriguez">Léa Rodriguez</name><affiliation><nlm:affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</nlm:affiliation></affiliation></author><author><name sortKey="Chahinian, Henri" sort="Chahinian, Henri" uniqKey="Chahinian H" first="Henri" last="Chahinian">Henri Chahinian</name><affiliation><nlm:affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</nlm:affiliation></affiliation></author><author><name sortKey="Fantini, Jacques" sort="Fantini, Jacques" uniqKey="Fantini J" first="Jacques" last="Fantini">Jacques Fantini</name><affiliation><nlm:affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Scientific reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><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></front></TEI><pubmed><MedlineCitation Status="In-Data-Review" Owner="NLM"><PMID Version="1">27352802</PMID><DateCreated><Year>2016</Year><Month>06</Month><Day>29</Day></DateCreated><DateRevised><Year>2016</Year><Month>07</Month><Day>03</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">2045-2322</ISSN><JournalIssue CitedMedium="Internet"><Volume>6</Volume><PubDate><Year>2016</Year><Month>Jun</Month><Day>29</Day></PubDate></JournalIssue><Title>Scientific reports</Title><ISOAbbreviation>Sci Rep</ISOAbbreviation></Journal><ArticleTitle>Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein.</ArticleTitle><Pagination><MedlinePgn>28781</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1038/srep28781</ELocationID><Abstract><AbstractText>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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Di Scala</LastName><ForeName>Coralie</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yahi</LastName><ForeName>Nouara</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Boutemeur</LastName><ForeName>Sonia</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Flores</LastName><ForeName>Alessandra</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rodriguez</LastName><ForeName>Léa</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chahinian</LastName><ForeName>Henri</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fantini</LastName><ForeName>Jacques</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>06</Month><Day>29</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Sci Rep</MedlineTA><NlmUniqueID>101563288</NlmUniqueID><ISSNLinking>2045-2322</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><OtherID Source="NLM">PMC4926208</OtherID></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>03</Month><Day>23</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>06</Month><Day>08</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>6</Month><Day>30</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>6</Month><Day>30</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>6</Month><Day>30</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">27352802</ArticleId><ArticleId IdType="pii">srep28781</ArticleId><ArticleId IdType="doi">10.1038/srep28781</ArticleId><ArticleId IdType="pmc">PMC4926208</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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