Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models
alpha-Synuclein (alpha-syn) is a small lipid-binding protein involved in vesicle trafficking whose function is poorly characterized. It is of great interest to human biology and medicine because alpha-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson's...
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| Veröffentlicht in: | Disease models & mechanisms 2010-03, Vol.3 (3-4), p.194-208 |
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| creator | Su, Linhui Julie Auluck, Pavan K Outeiro, Tiago Fleming Yeger-Lotem, Esti Kritzer, Joshua A Tardiff, Daniel F Strathearn, Katherine E Liu, Fang Cao, Songsong Hamamichi, Shusei Hill, Kathryn J Caldwell, Kim A Bell, George W Fraenkel, Ernest Cooper, Antony A Caldwell, Guy A McCaffery, J Michael Rochet, Jean-Christophe Lindquist, Susan |
| description | alpha-Synuclein (alpha-syn) is a small lipid-binding protein involved in vesicle trafficking whose function is poorly characterized. It is of great interest to human biology and medicine because alpha-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson's disease (PD). We previously created a yeast model of alpha-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to alpha-syn expression. We also uncovered a core group of proteins with diverse activities related to alpha-syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of alpha-syn also exhibits strong defects in mitochondrial function. Unlike our previous strain, genetic suppression of endoplasmic reticulum (ER)-to-Golgi trafficking alone does not suppress alpha-syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of alpha-syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced alpha-syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of alpha-syn foci, re-established ER-to-Golgi trafficking and ameliorated alpha-syn-mediated damage to mitochondria. They also corrected the toxicity of alpha-syn in nematode neurons and in primary rat neuronal midbrain cultures. Remarkably, the compounds also protected neurons against rotenone-induced toxicity, which has been used to model the mitochondrial defects associated with PD in humans. That single compounds are capable of rescuing the diverse toxicities of alpha-syn in yeast and neurons suggests that they are acting on deeply rooted biological processes that connect these toxicities and have been conserved for a billion years of eukaryotic evolution. Thus, it seems possible to develop novel therapeutic strategies to simultaneously target the multiple pathological features of PD. |
| doi_str_mv | 10.1242/dmm.004267 |
| format | Article |
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It is of great interest to human biology and medicine because alpha-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson's disease (PD). We previously created a yeast model of alpha-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to alpha-syn expression. We also uncovered a core group of proteins with diverse activities related to alpha-syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of alpha-syn also exhibits strong defects in mitochondrial function. Unlike our previous strain, genetic suppression of endoplasmic reticulum (ER)-to-Golgi trafficking alone does not suppress alpha-syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of alpha-syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced alpha-syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of alpha-syn foci, re-established ER-to-Golgi trafficking and ameliorated alpha-syn-mediated damage to mitochondria. They also corrected the toxicity of alpha-syn in nematode neurons and in primary rat neuronal midbrain cultures. Remarkably, the compounds also protected neurons against rotenone-induced toxicity, which has been used to model the mitochondrial defects associated with PD in humans. That single compounds are capable of rescuing the diverse toxicities of alpha-syn in yeast and neurons suggests that they are acting on deeply rooted biological processes that connect these toxicities and have been conserved for a billion years of eukaryotic evolution. Thus, it seems possible to develop novel therapeutic strategies to simultaneously target the multiple pathological features of PD.</description><identifier>ISSN: 1754-8403</identifier><identifier>EISSN: 1754-8411</identifier><identifier>DOI: 10.1242/dmm.004267</identifier><identifier>PMID: 20038714</identifier><language>eng</language><publisher>England: The Company of Biologists Ltd</publisher><subject>alpha-Synuclein - toxicity ; Animals ; Antiparkinson Agents - pharmacology ; Antiparkinson Agents - therapeutic use ; Caenorhabditis elegans - drug effects ; Caenorhabditis elegans - metabolism ; Dementia ; Disease Models, Animal ; Dopamine - metabolism ; Drug Evaluation, Preclinical ; Endoplasmic Reticulum - drug effects ; Endoplasmic Reticulum - metabolism ; Endoplasmic Reticulum - ultrastructure ; Gene Expression Profiling ; Genes ; Genomes ; Golgi Apparatus - drug effects ; Golgi Apparatus - metabolism ; Golgi Apparatus - ultrastructure ; Kinases ; Lipids ; Metabolism ; Mitochondria - drug effects ; Mitochondria - pathology ; Mitochondria - ultrastructure ; Mutation ; Neurons - drug effects ; Neurons - pathology ; Oxidative stress ; Parkinson Disease - drug therapy ; Parkinson Disease - metabolism ; Parkinson's disease ; Pathogenesis ; Protein Transport - drug effects ; Proteins ; Rats ; Reactive Oxygen Species - metabolism ; Rotenone - toxicity ; Saccharomyces cerevisiae - drug effects ; Stress, Physiological - drug effects ; Structure-Activity Relationship ; Toxicity</subject><ispartof>Disease models & mechanisms, 2010-03, Vol.3 (3-4), p.194-208</ispartof><rights>2010. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the associated terms available at https://journals.biologists.com/dmm/pages/rights-permissions .</rights><rights>2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c405t-862b0ce89524fdd71b00c8c06c2814241a4e3e5e2292c134235988557d89aa953</citedby><cites>FETCH-LOGICAL-c405t-862b0ce89524fdd71b00c8c06c2814241a4e3e5e2292c134235988557d89aa953</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869493/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869493/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20038714$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Su, Linhui Julie</creatorcontrib><creatorcontrib>Auluck, Pavan K</creatorcontrib><creatorcontrib>Outeiro, Tiago Fleming</creatorcontrib><creatorcontrib>Yeger-Lotem, Esti</creatorcontrib><creatorcontrib>Kritzer, Joshua A</creatorcontrib><creatorcontrib>Tardiff, Daniel F</creatorcontrib><creatorcontrib>Strathearn, Katherine E</creatorcontrib><creatorcontrib>Liu, Fang</creatorcontrib><creatorcontrib>Cao, Songsong</creatorcontrib><creatorcontrib>Hamamichi, Shusei</creatorcontrib><creatorcontrib>Hill, Kathryn J</creatorcontrib><creatorcontrib>Caldwell, Kim A</creatorcontrib><creatorcontrib>Bell, George W</creatorcontrib><creatorcontrib>Fraenkel, Ernest</creatorcontrib><creatorcontrib>Cooper, Antony A</creatorcontrib><creatorcontrib>Caldwell, Guy A</creatorcontrib><creatorcontrib>McCaffery, J Michael</creatorcontrib><creatorcontrib>Rochet, Jean-Christophe</creatorcontrib><creatorcontrib>Lindquist, Susan</creatorcontrib><title>Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models</title><title>Disease models & mechanisms</title><addtitle>Dis Model Mech</addtitle><description>alpha-Synuclein (alpha-syn) is a small lipid-binding protein involved in vesicle trafficking whose function is poorly characterized. It is of great interest to human biology and medicine because alpha-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson's disease (PD). We previously created a yeast model of alpha-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to alpha-syn expression. We also uncovered a core group of proteins with diverse activities related to alpha-syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of alpha-syn also exhibits strong defects in mitochondrial function. Unlike our previous strain, genetic suppression of endoplasmic reticulum (ER)-to-Golgi trafficking alone does not suppress alpha-syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of alpha-syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced alpha-syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of alpha-syn foci, re-established ER-to-Golgi trafficking and ameliorated alpha-syn-mediated damage to mitochondria. They also corrected the toxicity of alpha-syn in nematode neurons and in primary rat neuronal midbrain cultures. Remarkably, the compounds also protected neurons against rotenone-induced toxicity, which has been used to model the mitochondrial defects associated with PD in humans. That single compounds are capable of rescuing the diverse toxicities of alpha-syn in yeast and neurons suggests that they are acting on deeply rooted biological processes that connect these toxicities and have been conserved for a billion years of eukaryotic evolution. Thus, it seems possible to develop novel therapeutic strategies to simultaneously target the multiple pathological features of PD.</description><subject>alpha-Synuclein - toxicity</subject><subject>Animals</subject><subject>Antiparkinson Agents - pharmacology</subject><subject>Antiparkinson Agents - therapeutic use</subject><subject>Caenorhabditis elegans - drug effects</subject><subject>Caenorhabditis elegans - metabolism</subject><subject>Dementia</subject><subject>Disease Models, Animal</subject><subject>Dopamine - metabolism</subject><subject>Drug Evaluation, Preclinical</subject><subject>Endoplasmic Reticulum - drug effects</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>Endoplasmic Reticulum - ultrastructure</subject><subject>Gene Expression Profiling</subject><subject>Genes</subject><subject>Genomes</subject><subject>Golgi Apparatus - drug effects</subject><subject>Golgi Apparatus - metabolism</subject><subject>Golgi Apparatus - ultrastructure</subject><subject>Kinases</subject><subject>Lipids</subject><subject>Metabolism</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - pathology</subject><subject>Mitochondria - ultrastructure</subject><subject>Mutation</subject><subject>Neurons - drug effects</subject><subject>Neurons - pathology</subject><subject>Oxidative stress</subject><subject>Parkinson Disease - drug therapy</subject><subject>Parkinson Disease - metabolism</subject><subject>Parkinson's disease</subject><subject>Pathogenesis</subject><subject>Protein Transport - drug effects</subject><subject>Proteins</subject><subject>Rats</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Rotenone - toxicity</subject><subject>Saccharomyces cerevisiae - drug effects</subject><subject>Stress, Physiological - drug effects</subject><subject>Structure-Activity Relationship</subject><subject>Toxicity</subject><issn>1754-8403</issn><issn>1754-8411</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpVkd1q3DAQhUVoyf9NHqAIelEoONWfbekmEJY0LQRaSnMtZGm8q9SSNpIdyHP0hauw6dJezcCc-eYMB6ELSi4pE-yTC-GSEMG6_gAd074VjRSUvtn3hB-hk1IeCOmY5OoQHTFCuOypOEa_Vyls0xJdwWNOAZuIlzh4U8Bhu4HgrZlwsRkg4gxPkAvgIc0bfPOjmVNzm6a1x3M24-jtLx_X2MEIdi4V5HDwc7KbFF32leKey7hEO_sUsY_4u8l1oaT4oWDnC9STOCQHUzlDb0czFTh_rafo_vPNz9WX5u7b7dfV9V1jBWnnRnZsIBakapkYnevpQIiVlnSWSSqYoEYAhxYYU8xSLhhvlZRt2zupjFEtP0VXO-52GQI4C7E-Mult9sHkZ52M1_9Pot_odXrSTHZKKF4B718BOT0uUGb9kJYcq2fNOsW46HupqurjTmVzKiXDuL9AiX4JUNcA9S7AKn73r6e99G9i_A_kmpli</recordid><startdate>20100301</startdate><enddate>20100301</enddate><creator>Su, Linhui Julie</creator><creator>Auluck, Pavan K</creator><creator>Outeiro, Tiago Fleming</creator><creator>Yeger-Lotem, Esti</creator><creator>Kritzer, Joshua A</creator><creator>Tardiff, Daniel F</creator><creator>Strathearn, Katherine E</creator><creator>Liu, Fang</creator><creator>Cao, Songsong</creator><creator>Hamamichi, Shusei</creator><creator>Hill, Kathryn J</creator><creator>Caldwell, Kim A</creator><creator>Bell, George W</creator><creator>Fraenkel, Ernest</creator><creator>Cooper, Antony A</creator><creator>Caldwell, Guy A</creator><creator>McCaffery, J Michael</creator><creator>Rochet, Jean-Christophe</creator><creator>Lindquist, Susan</creator><general>The Company of Biologists Ltd</general><general>The Company of Biologists Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20100301</creationdate><title>Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models</title><author>Su, Linhui Julie ; Auluck, Pavan K ; Outeiro, Tiago Fleming ; Yeger-Lotem, Esti ; Kritzer, Joshua A ; Tardiff, Daniel F ; Strathearn, Katherine E ; Liu, Fang ; Cao, Songsong ; Hamamichi, Shusei ; Hill, Kathryn J ; Caldwell, Kim A ; Bell, George W ; Fraenkel, Ernest ; Cooper, Antony A ; Caldwell, Guy A ; McCaffery, J Michael ; Rochet, Jean-Christophe ; Lindquist, Susan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c405t-862b0ce89524fdd71b00c8c06c2814241a4e3e5e2292c134235988557d89aa953</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>alpha-Synuclein - 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It is of great interest to human biology and medicine because alpha-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson's disease (PD). We previously created a yeast model of alpha-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to alpha-syn expression. We also uncovered a core group of proteins with diverse activities related to alpha-syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of alpha-syn also exhibits strong defects in mitochondrial function. Unlike our previous strain, genetic suppression of endoplasmic reticulum (ER)-to-Golgi trafficking alone does not suppress alpha-syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of alpha-syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced alpha-syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of alpha-syn foci, re-established ER-to-Golgi trafficking and ameliorated alpha-syn-mediated damage to mitochondria. They also corrected the toxicity of alpha-syn in nematode neurons and in primary rat neuronal midbrain cultures. Remarkably, the compounds also protected neurons against rotenone-induced toxicity, which has been used to model the mitochondrial defects associated with PD in humans. That single compounds are capable of rescuing the diverse toxicities of alpha-syn in yeast and neurons suggests that they are acting on deeply rooted biological processes that connect these toxicities and have been conserved for a billion years of eukaryotic evolution. Thus, it seems possible to develop novel therapeutic strategies to simultaneously target the multiple pathological features of PD.</abstract><cop>England</cop><pub>The Company of Biologists Ltd</pub><pmid>20038714</pmid><doi>10.1242/dmm.004267</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1754-8403 |
| ispartof | Disease models & mechanisms, 2010-03, Vol.3 (3-4), p.194-208 |
| issn | 1754-8403 1754-8411 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2869493 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | alpha-Synuclein - toxicity Animals Antiparkinson Agents - pharmacology Antiparkinson Agents - therapeutic use Caenorhabditis elegans - drug effects Caenorhabditis elegans - metabolism Dementia Disease Models, Animal Dopamine - metabolism Drug Evaluation, Preclinical Endoplasmic Reticulum - drug effects Endoplasmic Reticulum - metabolism Endoplasmic Reticulum - ultrastructure Gene Expression Profiling Genes Genomes Golgi Apparatus - drug effects Golgi Apparatus - metabolism Golgi Apparatus - ultrastructure Kinases Lipids Metabolism Mitochondria - drug effects Mitochondria - pathology Mitochondria - ultrastructure Mutation Neurons - drug effects Neurons - pathology Oxidative stress Parkinson Disease - drug therapy Parkinson Disease - metabolism Parkinson's disease Pathogenesis Protein Transport - drug effects Proteins Rats Reactive Oxygen Species - metabolism Rotenone - toxicity Saccharomyces cerevisiae - drug effects Stress, Physiological - drug effects Structure-Activity Relationship Toxicity |
| title | Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T18%3A11%3A14IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Compounds%20from%20an%20unbiased%20chemical%20screen%20reverse%20both%20ER-to-Golgi%20trafficking%20defects%20and%20mitochondrial%20dysfunction%20in%20Parkinson's%20disease%20models&rft.jtitle=Disease%20models%20&%20mechanisms&rft.au=Su,%20Linhui%20Julie&rft.date=2010-03-01&rft.volume=3&rft.issue=3-4&rft.spage=194&rft.epage=208&rft.pages=194-208&rft.issn=1754-8403&rft.eissn=1754-8411&rft_id=info:doi/10.1242/dmm.004267&rft_dat=%3Cproquest_pubme%3E2692347789%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2692347789&rft_id=info:pmid/20038714&rfr_iscdi=true |