Repurposing doxycycline for synucleinopathies: remodelling of α-synuclein oligomers towards non-toxic parallel beta-sheet structured species
Identifieur interne : 000012 ( Main/Exploration ); précédent : 000011; suivant : 000013Repurposing doxycycline for synucleinopathies: remodelling of α-synuclein oligomers towards non-toxic parallel beta-sheet structured species
Auteurs : Florencia González-Lizárraga [Argentine, France] ; Sergio B. Socías [Argentine] ; César L. Ávila [Argentine] ; Clarisa M. Torres-Bugeau [Argentine] ; Leandro R. S. Barbosa [Brésil] ; Andres Binolfi [Argentine] ; Julia E. Sepúlveda-Díaz [France] ; Elaine Del-Bel [Brésil] ; Claudio O. Fernandez [Argentine] ; Dulce Papy-Garcia [France] ; Rosangela Itri [Brésil] ; Rita Raisman-Vozari [France] ; Rosana N. Chehín [Argentine]Source :
- Scientific Reports [ 2045-2322 ] ; 2017.
Abstract
Synucleinophaties are progressive neurodegenerative disorders with no cure to date. An attractive strategy to tackle this problem is repurposing already tested safe drugs against novel targets. In this way, doxycycline prevents neurodegeneration in Parkinson models by modulating neuroinflammation. However, anti-inflammatory therapy
Url:
DOI: 10.1038/srep41755
PubMed: 28155912
PubMed Central: 5290535
Affiliations:
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Socías</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Instituto Superior de Investigaciones Biológicas (INSIBIO), CCT-Tucumán and Instituto de Química Biológica Dr Bernabé Bloj (CONICET-UNT)</institution>, Chacabuco 461 (T4000ILI) Tucumán,<country>Argentina</country></nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Avila, Cesar L" sort="Avila, Cesar L" uniqKey="Avila C" first="César L." last="Ávila">César L. Ávila</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Instituto Superior de Investigaciones Biológicas (INSIBIO), CCT-Tucumán and Instituto de Química Biológica Dr Bernabé Bloj (CONICET-UNT)</institution>, Chacabuco 461 (T4000ILI) Tucumán,<country>Argentina</country></nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Torres Bugeau, Clarisa M" sort="Torres Bugeau, Clarisa M" uniqKey="Torres Bugeau C" first="Clarisa M." last="Torres-Bugeau">Clarisa M. Torres-Bugeau</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Instituto Superior de Investigaciones Biológicas (INSIBIO), CCT-Tucumán and Instituto de Química Biológica Dr Bernabé Bloj (CONICET-UNT)</institution>, Chacabuco 461 (T4000ILI) Tucumán,<country>Argentina</country></nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Barbosa, Leandro R S" sort="Barbosa, Leandro R S" uniqKey="Barbosa L" first="Leandro R. S." last="Barbosa">Leandro R. S. Barbosa</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Instituto de Física da Universidade de São Paulo – IFUSP</institution>, Rua do Matão, Travessa R, 187, São Paulo,<country>Brazil</country></nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Binolfi, Andres" sort="Binolfi, Andres" uniqKey="Binolfi A" first="Andres" last="Binolfi">Andres Binolfi</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC) and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET), Universidad Nacional de Rosario</institution>, Ocampo y Esmeralda, S2002LRK Rosario,<country>Argentina</country></nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sepulveda Diaz, Julia E" sort="Sepulveda Diaz, Julia E" uniqKey="Sepulveda Diaz J" first="Julia E." last="Sepúlveda-Díaz">Julia E. Sepúlveda-Díaz</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Institut National De La Santé Et De La Recherche Médicale, U 1127, CNRS, Unité Mixte De Recherche (UMR) 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut Du Cerveau Et De La Moelle Epinière</institution>, ICM, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Del Bel, Elaine" sort="Del Bel, Elaine" uniqKey="Del Bel E" first="Elaine" last="Del-Bel">Elaine Del-Bel</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Morphology, Physiology and Stomatology, Faculty of Odontology of Ribeirão Preto, University of São Paulo, Brazil, Center of Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo</institution>,<country>Brazil</country></nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fernandez, Claudio O" sort="Fernandez, Claudio O" uniqKey="Fernandez C" first="Claudio O." last="Fernandez">Claudio O. Fernandez</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC) and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET), Universidad Nacional de Rosario</institution>, Ocampo y Esmeralda, S2002LRK Rosario,<country>Argentina</country></nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Papy Garcia, Dulce" sort="Papy Garcia, Dulce" uniqKey="Papy Garcia D" first="Dulce" last="Papy-Garcia">Dulce Papy-Garcia</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Laboratoire Croissance, Réparation et Régénération Tissulaires (CRRET), CNRS ERL 9215, Université Paris Est Créteil, Université Paris Est</institution>, F-94000, Créteil,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Itri, Rosangela" sort="Itri, Rosangela" uniqKey="Itri R" first="Rosangela" last="Itri">Rosangela Itri</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Instituto de Física da Universidade de São Paulo – IFUSP</institution>, Rua do Matão, Travessa R, 187, São Paulo,<country>Brazil</country></nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Raisman Vozari, Rita" sort="Raisman Vozari, Rita" uniqKey="Raisman Vozari R" first="Rita" last="Raisman-Vozari">Rita Raisman-Vozari</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Institut National De La Santé Et De La Recherche Médicale, U 1127, CNRS, Unité Mixte De Recherche (UMR) 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut Du Cerveau Et De La Moelle Epinière</institution>, ICM, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Chehin, Rosana N" sort="Chehin, Rosana N" uniqKey="Chehin R" first="Rosana N." last="Chehín">Rosana N. Chehín</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Instituto Superior de Investigaciones Biológicas (INSIBIO), CCT-Tucumán and Instituto de Química Biológica Dr Bernabé Bloj (CONICET-UNT)</institution>, Chacabuco 461 (T4000ILI) Tucumán,<country>Argentina</country></nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Synucleinophaties are progressive neurodegenerative disorders with no cure to date. An attractive strategy to tackle this problem is repurposing already tested safe drugs against novel targets. In this way, doxycycline prevents neurodegeneration in Parkinson models by modulating neuroinflammation. However, anti-inflammatory therapy <italic>per se</italic> is insufficient to account for neuroprotection. Herein we characterise novel targets of doxycycline describing the structural background supporting its effectiveness as a neuroprotector at subantibiotic doses. Our results show that doxycycline reshapes α-synuclein oligomers into off-pathway, high-molecular-weight species that do not evolve into fibrils. Off-pathway species present less hydrophobic surface than on-pathway oligomers and display different β-sheet structural arrangement. These structural changes affect the α-synuclein ability to destabilize biological membranes, cell viability, and formation of additional toxic species. Altogether, these mechanisms could act synergically giving novel targets for repurposing this drug.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Duda, J E" uniqKey="Duda J">J. E. Duda</name></author><author><name sortKey="Lee, V M" uniqKey="Lee V">V. M. Lee</name></author><author><name sortKey="Trojanowski, J Q" uniqKey="Trojanowski J">J. Q. Trojanowski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spillantini, M G" uniqKey="Spillantini M">M. G. Spillantini</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spillantini, M G" uniqKey="Spillantini M">M. G. Spillantini</name></author><author><name sortKey="Crowther, R A" uniqKey="Crowther R">R. A. Crowther</name></author><author><name sortKey="Jakes, R" uniqKey="Jakes R">R. Jakes</name></author><author><name sortKey="Hasegawa, M" uniqKey="Hasegawa M">M. 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Hauser</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Argentine</li><li>Brésil</li><li>France</li></country></list><tree><country name="Argentine"><noRegion><name sortKey="Gonzalez Lizarraga, Florencia" sort="Gonzalez Lizarraga, Florencia" uniqKey="Gonzalez Lizarraga F" first="Florencia" last="González-Lizárraga">Florencia González-Lizárraga</name></noRegion><name sortKey="Avila, Cesar L" sort="Avila, Cesar L" uniqKey="Avila C" first="César L." last="Ávila">César L. Ávila</name><name sortKey="Binolfi, Andres" sort="Binolfi, Andres" uniqKey="Binolfi A" first="Andres" last="Binolfi">Andres Binolfi</name><name sortKey="Chehin, Rosana N" sort="Chehin, Rosana N" uniqKey="Chehin R" first="Rosana N." last="Chehín">Rosana N. Chehín</name><name sortKey="Fernandez, Claudio O" sort="Fernandez, Claudio O" uniqKey="Fernandez C" first="Claudio O." last="Fernandez">Claudio O. Fernandez</name><name sortKey="Socias, Sergio B" sort="Socias, Sergio B" uniqKey="Socias S" first="Sergio B." last="Socías">Sergio B. Socías</name><name sortKey="Torres Bugeau, Clarisa M" sort="Torres Bugeau, Clarisa M" uniqKey="Torres Bugeau C" first="Clarisa M." last="Torres-Bugeau">Clarisa M. Torres-Bugeau</name></country><country name="France"><noRegion><name sortKey="Gonzalez Lizarraga, Florencia" sort="Gonzalez Lizarraga, Florencia" uniqKey="Gonzalez Lizarraga F" first="Florencia" last="González-Lizárraga">Florencia González-Lizárraga</name></noRegion><name sortKey="Papy Garcia, Dulce" sort="Papy Garcia, Dulce" uniqKey="Papy Garcia D" first="Dulce" last="Papy-Garcia">Dulce Papy-Garcia</name><name sortKey="Raisman Vozari, Rita" sort="Raisman Vozari, Rita" uniqKey="Raisman Vozari R" first="Rita" last="Raisman-Vozari">Rita Raisman-Vozari</name><name sortKey="Sepulveda Diaz, Julia E" sort="Sepulveda Diaz, Julia E" uniqKey="Sepulveda Diaz J" first="Julia E." last="Sepúlveda-Díaz">Julia E. Sepúlveda-Díaz</name></country><country name="Brésil"><noRegion><name sortKey="Barbosa, Leandro R S" sort="Barbosa, Leandro R S" uniqKey="Barbosa L" first="Leandro R. S." last="Barbosa">Leandro R. S. Barbosa</name></noRegion><name sortKey="Del Bel, Elaine" sort="Del Bel, Elaine" uniqKey="Del Bel E" first="Elaine" last="Del-Bel">Elaine Del-Bel</name><name sortKey="Itri, Rosangela" sort="Itri, Rosangela" uniqKey="Itri R" first="Rosangela" last="Itri">Rosangela Itri</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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