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dc.contributor.author
Tóth, Gergely
dc.contributor.author
Neumann, Thomas
dc.contributor.author
Berthet, Amandine
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Masliah, Eliezer
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Spencer, Brian
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Tao, Jiahui
dc.contributor.author
Jobling, Michael F.
dc.contributor.author
Gardai, Shyra J.
dc.contributor.author
Bertoncini, Carlos Walter
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dc.contributor.author
Cremades, Nunilo
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Bova, Michael
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Ballaron, Stephen
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Chen, Xiao-Hua
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Mao, Wenxian
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Nguyen, Phuong
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Tabios, Mariano C.
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Tambe, Mitali A.
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Rochet, Jean Christophe
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Junker, Hans Dieter
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Schwizer, Daniel
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Sekul, Renate
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Ott, Inge
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Anderson, John P.
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Szoke, Balazs
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Hoffman, Wherly
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Christodoulou, John
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Yednock, Ted
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Agard, David A.
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Schenk, Dale
dc.contributor.author
McConlogue, Lisa
dc.date.available
2022-10-31T16:21:24Z
dc.date.issued
2019-11
dc.identifier.citation
Tóth, Gergely; Neumann, Thomas; Berthet, Amandine; Masliah, Eliezer; Spencer, Brian; et al.; Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions; Nature Publishing Group; Scientific Reports; 9; 1; 11-2019; 1-14
dc.identifier.uri
http://hdl.handle.net/11336/175630
dc.description.abstract
The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Nature Publishing Group
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by/2.5/ar/
dc.subject
PARKINSONS DISEASE
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DRUG DISCOVERY
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STRUCTURAL BIOLOGY
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NEURODEGENERATION
dc.subject.classification
Biofísica
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dc.subject.classification
Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
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Métodos de Investigación en Bioquímica
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2022-10-27T10:25:50Z
dc.identifier.eissn
2045-2322
dc.journal.volume
9
dc.journal.number
1
dc.journal.pagination
1-14
dc.journal.pais
Alemania
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dc.journal.ciudad
Berlín
dc.description.fil
Fil: Tóth, Gergely. Elan Pharmaceuticals; Estados Unidos. University of Cambridge; Estados Unidos. Hungarian Academy of Sciences; Hungría. Cantabio Pharmaceuticals; Estados Unidos
dc.description.fil
Fil: Neumann, Thomas. NovAliX; Francia
dc.description.fil
Fil: Berthet, Amandine. Gladstone Institute of Neurological Disease; Estados Unidos
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Fil: Masliah, Eliezer. University of California at San Diego; Estados Unidos. National Institutes of Health; Estados Unidos
dc.description.fil
Fil: Spencer, Brian. University of California at San Diego; Estados Unidos
dc.description.fil
Fil: Tao, Jiahui. University of California; Estados Unidos
dc.description.fil
Fil: Jobling, Michael F.. Elan Pharmaceuticals; Estados Unidos
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Fil: Gardai, Shyra J.. Elan Pharmaceuticals; Estados Unidos
dc.description.fil
Fil: Bertoncini, Carlos Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. University of Cambridge; Reino Unido. Institute for Research in Biomedicine; España
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Fil: Cremades, Nunilo. University of Cambridge; Reino Unido
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Fil: Bova, Michael. Elan Pharmaceuticals; Estados Unidos
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Fil: Ballaron, Stephen. Elan Pharmaceuticals; Estados Unidos
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Fil: Chen, Xiao-Hua. Elan Pharmaceuticals; Estados Unidos
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Fil: Mao, Wenxian. Elan Pharmaceuticals; Estados Unidos
dc.description.fil
Fil: Nguyen, Phuong. University of California; Estados Unidos
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Fil: Tabios, Mariano C.. University of California; Estados Unidos
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Fil: Tambe, Mitali A.. Purdue University; Estados Unidos
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Fil: Rochet, Jean Christophe. Purdue University; Estados Unidos
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Fil: Junker, Hans Dieter. Aalen University; Alemania. NovAliX; Francia
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Fil: Schwizer, Daniel. NovAliX; Francia
dc.description.fil
Fil: Sekul, Renate. NovAliX; Francia
dc.description.fil
Fil: Ott, Inge. NovAliX; Francia
dc.description.fil
Fil: Anderson, John P.. Elan Pharmaceuticals; Estados Unidos
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Fil: Szoke, Balazs. Elan Pharmaceuticals; Estados Unidos
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Fil: Hoffman, Wherly. Elan Pharmaceuticals; Estados Unidos
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Fil: Christodoulou, John. Colegio Universitario de Londres; Reino Unido
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Fil: Yednock, Ted. Elan Pharmaceuticals; Estados Unidos
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Fil: Agard, David A.. University of California; Estados Unidos
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Fil: Schenk, Dale. Elan Pharmaceuticals; Estados Unidos
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Fil: McConlogue, Lisa. Elan Pharmaceuticals; Estados Unidos. Gladstone Institute of Neurological Disease; Estados Unidos. University of California; Estados Unidos
dc.journal.title
Scientific Reports
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-019-52598-4
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1038/s41598-019-52598-4
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