From yeast to patient neurons and back again: powerful new discovery platform.
Identifieur interne : 000587 ( PubMed/Checkpoint ); précédent : 000586; suivant : 000588From yeast to patient neurons and back again: powerful new discovery platform.
Auteurs : Daniel F. Tardiff [États-Unis] ; Vikram Khurana ; Chee Yeun Chung ; Susan LindquistSource :
- Movement disorders : official journal of the Movement Disorder Society [ 1531-8257 ] ; 2014.
English descriptors
- KwdEn :
- MESH :
- chemical , genetics : alpha-Synuclein.
- genetics : Movement Disorders, Yeasts.
- metabolism : Neurons, Yeasts, alpha-Synuclein.
- pathology : Movement Disorders.
- Animals, Humans, Translational Medical Research.
Abstract
No disease-modifying therapies are available for synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA). The lack of therapies has been impeded by a paucity of validated drug targets and problematic cell-based model systems. New approaches are therefore needed to identify genes and compounds that directly target the underlying cellular pathologies elicited by the pathological protein, α-synuclein (α-syn). This small, lipid-binding protein impinges on evolutionarily conserved processes such as vesicle trafficking and mitochondrial function. For decades, the genetically tractable, single-cell eukaryote, budding yeast, has been used to study nearly all aspects of cell biology. More recently, yeast has revealed key insights into the underlying cellular pathologies caused by α-syn. The robust cellular toxicity caused by α-syn expression facilitates unbiased high-throughput small-molecule screening. Critically, one must validate the discoveries made in yeast in disease-relevant neuronal models. Here, we describe two recent reports that together establish yeast-to-human discovery platforms for synucleinopathies. In this exemplar, genes and small molecules identified in yeast were validated in patient-derived neurons that present the same cellular phenotypes initially discovered in yeast. On validation, we returned to yeast, where unparalleled genetic approaches facilitated the elucidation of a small molecule's mode of action. This approach enabled the identification and neuronal validation of a previously unknown "druggable" node that interfaces with the underlying, precipitating pathologies caused by α-syn. Such platforms can provide sorely needed leads and fresh ideas for disease-modifying therapy for these devastating diseases.
DOI: 10.1002/mds.25989
PubMed: 25131316
Affiliations:
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Tardiff</name><affiliation wicri:level="2"><nlm:affiliation>Whitehead Institute for Biomedical Research (WIBR), Cambridge, Massachusetts, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Whitehead Institute for Biomedical Research (WIBR), Cambridge, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Khurana, Vikram" sort="Khurana, Vikram" uniqKey="Khurana V" first="Vikram" last="Khurana">Vikram Khurana</name></author><author><name sortKey="Chung, Chee Yeun" sort="Chung, Chee Yeun" uniqKey="Chung C" first="Chee Yeun" last="Chung">Chee Yeun Chung</name></author><author><name sortKey="Lindquist, Susan" sort="Lindquist, Susan" uniqKey="Lindquist S" first="Susan" last="Lindquist">Susan Lindquist</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:25131316</idno><idno type="pmid">25131316</idno><idno type="doi">10.1002/mds.25989</idno><idno type="wicri:Area/PubMed/Corpus">000422</idno><idno type="wicri:Area/PubMed/Curation">000422</idno><idno type="wicri:Area/PubMed/Checkpoint">000587</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">From yeast to patient neurons and back again: powerful new discovery platform.</title><author><name sortKey="Tardiff, Daniel F" sort="Tardiff, Daniel F" uniqKey="Tardiff D" first="Daniel F" last="Tardiff">Daniel F. Tardiff</name><affiliation wicri:level="2"><nlm:affiliation>Whitehead Institute for Biomedical Research (WIBR), Cambridge, Massachusetts, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Whitehead Institute for Biomedical Research (WIBR), Cambridge, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Khurana, Vikram" sort="Khurana, Vikram" uniqKey="Khurana V" first="Vikram" last="Khurana">Vikram Khurana</name></author><author><name sortKey="Chung, Chee Yeun" sort="Chung, Chee Yeun" uniqKey="Chung C" first="Chee Yeun" last="Chung">Chee Yeun Chung</name></author><author><name sortKey="Lindquist, Susan" sort="Lindquist, Susan" uniqKey="Lindquist S" first="Susan" last="Lindquist">Susan Lindquist</name></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="eISSN">1531-8257</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Humans</term><term>Movement Disorders (genetics)</term><term>Movement Disorders (pathology)</term><term>Neurons (metabolism)</term><term>Translational Medical Research</term><term>Yeasts (genetics)</term><term>Yeasts (metabolism)</term><term>alpha-Synuclein (genetics)</term><term>alpha-Synuclein (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Movement Disorders</term><term>Yeasts</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Neurons</term><term>Yeasts</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Movement Disorders</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Humans</term><term>Translational Medical Research</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">No disease-modifying therapies are available for synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA). The lack of therapies has been impeded by a paucity of validated drug targets and problematic cell-based model systems. New approaches are therefore needed to identify genes and compounds that directly target the underlying cellular pathologies elicited by the pathological protein, α-synuclein (α-syn). This small, lipid-binding protein impinges on evolutionarily conserved processes such as vesicle trafficking and mitochondrial function. For decades, the genetically tractable, single-cell eukaryote, budding yeast, has been used to study nearly all aspects of cell biology. More recently, yeast has revealed key insights into the underlying cellular pathologies caused by α-syn. The robust cellular toxicity caused by α-syn expression facilitates unbiased high-throughput small-molecule screening. Critically, one must validate the discoveries made in yeast in disease-relevant neuronal models. Here, we describe two recent reports that together establish yeast-to-human discovery platforms for synucleinopathies. In this exemplar, genes and small molecules identified in yeast were validated in patient-derived neurons that present the same cellular phenotypes initially discovered in yeast. On validation, we returned to yeast, where unparalleled genetic approaches facilitated the elucidation of a small molecule's mode of action. This approach enabled the identification and neuronal validation of a previously unknown "druggable" node that interfaces with the underlying, precipitating pathologies caused by α-syn. Such platforms can provide sorely needed leads and fresh ideas for disease-modifying therapy for these devastating diseases.</div></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">25131316</PMID><DateCreated><Year>2014</Year><Month>09</Month><Day>11</Day></DateCreated><DateCompleted><Year>2015</Year><Month>05</Month><Day>14</Day></DateCompleted><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1531-8257</ISSN><JournalIssue CitedMedium="Internet"><Volume>29</Volume><Issue>10</Issue><PubDate><Year>2014</Year><Month>Sep</Month></PubDate></JournalIssue><Title>Movement disorders : official journal of the Movement Disorder Society</Title><ISOAbbreviation>Mov. Disord.</ISOAbbreviation></Journal><ArticleTitle>From yeast to patient neurons and back again: powerful new discovery platform.</ArticleTitle><Pagination><MedlinePgn>1231-40</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1002/mds.25989</ELocationID><Abstract><AbstractText>No disease-modifying therapies are available for synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA). The lack of therapies has been impeded by a paucity of validated drug targets and problematic cell-based model systems. New approaches are therefore needed to identify genes and compounds that directly target the underlying cellular pathologies elicited by the pathological protein, α-synuclein (α-syn). This small, lipid-binding protein impinges on evolutionarily conserved processes such as vesicle trafficking and mitochondrial function. For decades, the genetically tractable, single-cell eukaryote, budding yeast, has been used to study nearly all aspects of cell biology. More recently, yeast has revealed key insights into the underlying cellular pathologies caused by α-syn. The robust cellular toxicity caused by α-syn expression facilitates unbiased high-throughput small-molecule screening. Critically, one must validate the discoveries made in yeast in disease-relevant neuronal models. Here, we describe two recent reports that together establish yeast-to-human discovery platforms for synucleinopathies. In this exemplar, genes and small molecules identified in yeast were validated in patient-derived neurons that present the same cellular phenotypes initially discovered in yeast. On validation, we returned to yeast, where unparalleled genetic approaches facilitated the elucidation of a small molecule's mode of action. This approach enabled the identification and neuronal validation of a previously unknown "druggable" node that interfaces with the underlying, precipitating pathologies caused by α-syn. Such platforms can provide sorely needed leads and fresh ideas for disease-modifying therapy for these devastating diseases.</AbstractText><CopyrightInformation>© 2014 International Parkinson and Movement Disorder Society.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Tardiff</LastName><ForeName>Daniel F</ForeName><Initials>DF</Initials><AffiliationInfo><Affiliation>Whitehead Institute for Biomedical Research (WIBR), Cambridge, Massachusetts, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Khurana</LastName><ForeName>Vikram</ForeName><Initials>V</Initials></Author><Author ValidYN="Y"><LastName>Chung</LastName><ForeName>Chee Yeun</ForeName><Initials>CY</Initials></Author><Author ValidYN="Y"><LastName>Lindquist</LastName><ForeName>Susan</ForeName><Initials>S</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>K01 AG038546</GrantID><Acronym>AG</Acronym><Agency>NIA NIH 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UI="D006801">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D009069">Movement Disorders</DescriptorName><QualifierName MajorTopicYN="N" UI="Q000235">genetics</QualifierName><QualifierName MajorTopicYN="Y" UI="Q000473">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D009474">Neurons</DescriptorName><QualifierName MajorTopicYN="Y" UI="Q000378">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="Y" UI="D057170">Translational Medical Research</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="Y" UI="D015003">Yeasts</DescriptorName><QualifierName MajorTopicYN="N" UI="Q000235">genetics</QualifierName><QualifierName MajorTopicYN="N" UI="Q000378">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D051844">alpha-Synuclein</DescriptorName><QualifierName MajorTopicYN="N" UI="Q000235">genetics</QualifierName><QualifierName MajorTopicYN="Y" UI="Q000378">metabolism</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Parkinson's disease</Keyword><Keyword MajorTopicYN="N">drug target identification</Keyword><Keyword MajorTopicYN="N">human iPS cells</Keyword><Keyword MajorTopicYN="N">phenotypic screen</Keyword><Keyword MajorTopicYN="N">yeast</Keyword><Keyword MajorTopicYN="N">α−synuclein</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2014</Year><Month>6</Month><Day>2</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2014</Year><Month>7</Month><Day>10</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2014</Year><Month>7</Month><Day>14</Day></PubMedPubDate><PubMedPubDate PubStatus="aheadofprint"><Year>2014</Year><Month>8</Month><Day>14</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2014</Year><Month>8</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2014</Year><Month>8</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2015</Year><Month>5</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">25131316</ArticleId><ArticleId IdType="doi">10.1002/mds.25989</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>États-Unis</li></country><region><li>Massachusetts</li></region></list><tree><noCountry><name sortKey="Chung, Chee Yeun" sort="Chung, Chee Yeun" uniqKey="Chung C" first="Chee Yeun" last="Chung">Chee Yeun Chung</name><name sortKey="Khurana, Vikram" sort="Khurana, Vikram" uniqKey="Khurana V" first="Vikram" last="Khurana">Vikram Khurana</name><name sortKey="Lindquist, Susan" sort="Lindquist, Susan" uniqKey="Lindquist S" first="Susan" last="Lindquist">Susan Lindquist</name></noCountry><country name="États-Unis"><region name="Massachusetts"><name sortKey="Tardiff, Daniel F" sort="Tardiff, Daniel F" uniqKey="Tardiff D" first="Daniel F" last="Tardiff">Daniel F. 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