Compounds from an Unbiased Chemical Screen Reverse Both Er-to-Golgi Trafficking Defects and Mitochondrial Dysfunction in Parkinson's Disease Models
α-Synuclein (α-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 α-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson’s disease (PD). We...
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Company of Biologists Limited
2011
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| Online Access: | http://hdl.handle.net/1721.1/66913 https://orcid.org/0000-0003-1307-882X https://orcid.org/0000-0001-9249-8181 |
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| author | Su, Linhui Julie Auluck, Pavan K. Outeiro, Tiago Fleming Yeger-Lotem, Esti Kritzer, Joshua A. Tardiff, Daniel F. Bell, George W. Fraenkel, Ernest Lindquist, Susan Strathearn, Katherine E. Liu, Fang Cao, Songsong Hamamichi, Shusei Hill, Kathryn J. Caldwell, Kim A. Cooper, Antony A. Caldwell, Guy A. McCaffery, J. Michael Rochet, Jean-Christophe |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Su, Linhui Julie Auluck, Pavan K. Outeiro, Tiago Fleming Yeger-Lotem, Esti Kritzer, Joshua A. Tardiff, Daniel F. Bell, George W. Fraenkel, Ernest Lindquist, Susan Strathearn, Katherine E. Liu, Fang Cao, Songsong Hamamichi, Shusei Hill, Kathryn J. Caldwell, Kim A. Cooper, Antony A. Caldwell, Guy A. McCaffery, J. Michael Rochet, Jean-Christophe |
| author_sort | Su, Linhui Julie |
| collection | MIT |
| description | α-Synuclein (α-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 α-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson’s disease (PD). We previously created a yeast model of α-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to α-syn expression. We also uncovered a core group of proteins with diverse activities related to α-syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of α-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 α-syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of α-syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced α-syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of α-syn foci, re-established ER-to-Golgi trafficking and ameliorated α-syn-mediated damage to mitochondria. They also corrected the toxicity of α-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 α-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. |
| first_indexed | 2024-09-23T15:00:21Z |
| format | Article |
| id | mit-1721.1/66913 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:00:21Z |
| publishDate | 2011 |
| publisher | Company of Biologists Limited |
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| spelling | mit-1721.1/669132022-09-29T11:59:28Z Compounds from an Unbiased Chemical Screen Reverse Both Er-to-Golgi Trafficking Defects and Mitochondrial Dysfunction in Parkinson's Disease Models Su, Linhui Julie Auluck, Pavan K. Outeiro, Tiago Fleming Yeger-Lotem, Esti Kritzer, Joshua A. Tardiff, Daniel F. Bell, George W. Fraenkel, Ernest Lindquist, Susan Strathearn, Katherine E. Liu, Fang Cao, Songsong Hamamichi, Shusei Hill, Kathryn J. Caldwell, Kim A. Cooper, Antony A. Caldwell, Guy A. McCaffery, J. Michael Rochet, Jean-Christophe Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Lindquist, Susan Su, Linhui Julie Auluck, Pavan K. Outeiro, Tiago Fleming Yeger-Lotem, Esti Kritzer, Joshua A. Tardiff, Daniel F. Bell, George W. Fraenkel, Ernest Lindquist, Susan α-Synuclein (α-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 α-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson’s disease (PD). We previously created a yeast model of α-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to α-syn expression. We also uncovered a core group of proteins with diverse activities related to α-syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of α-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 α-syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of α-syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced α-syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of α-syn foci, re-established ER-to-Golgi trafficking and ameliorated α-syn-mediated damage to mitochondria. They also corrected the toxicity of α-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 α-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. MGH/MIT Morris Udall Center of Excellence in Parkinson Disease Research (NS038372) Michael J. Fox Foundation for Parkinson's Research Howard Hughes Medical Institute United States. National Institutes of Health (NS049221) American Parkinson Disease Association, Inc. 2011-11-03T17:49:00Z 2011-11-03T17:49:00Z 2010-01 2009-09 Article http://purl.org/eprint/type/JournalArticle 1754-8403 1754-8411 http://hdl.handle.net/1721.1/66913 Su, L. J. et al. “Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson’s disease models.” Disease Models & Mechanisms 3 (2009): 194-208. Web. 3 Nov. 2011. © 2010 Company of Biologists Limited https://orcid.org/0000-0003-1307-882X https://orcid.org/0000-0001-9249-8181 en_US http://dx.doi.org/10.1242/dmm.004267 Disease Models and Mechanisms Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Company of Biologists Limited Lindquist |
| spellingShingle | Su, Linhui Julie Auluck, Pavan K. Outeiro, Tiago Fleming Yeger-Lotem, Esti Kritzer, Joshua A. Tardiff, Daniel F. Bell, George W. Fraenkel, Ernest Lindquist, Susan Strathearn, Katherine E. Liu, Fang Cao, Songsong Hamamichi, Shusei Hill, Kathryn J. Caldwell, Kim A. Cooper, Antony A. Caldwell, Guy A. McCaffery, J. Michael Rochet, Jean-Christophe Compounds from an Unbiased Chemical Screen Reverse Both Er-to-Golgi Trafficking Defects and Mitochondrial Dysfunction in Parkinson's Disease Models |
| title | Compounds from an Unbiased Chemical Screen Reverse Both Er-to-Golgi Trafficking Defects and Mitochondrial Dysfunction in Parkinson's Disease Models |
| title_full | Compounds from an Unbiased Chemical Screen Reverse Both Er-to-Golgi Trafficking Defects and Mitochondrial Dysfunction in Parkinson's Disease Models |
| title_fullStr | Compounds from an Unbiased Chemical Screen Reverse Both Er-to-Golgi Trafficking Defects and Mitochondrial Dysfunction in Parkinson's Disease Models |
| title_full_unstemmed | Compounds from an Unbiased Chemical Screen Reverse Both Er-to-Golgi Trafficking Defects and Mitochondrial Dysfunction in Parkinson's Disease Models |
| title_short | Compounds from an Unbiased Chemical Screen Reverse Both Er-to-Golgi Trafficking Defects and Mitochondrial Dysfunction in Parkinson's Disease Models |
| title_sort | compounds from an unbiased chemical screen reverse both er to golgi trafficking defects and mitochondrial dysfunction in parkinson s disease models |
| url | http://hdl.handle.net/1721.1/66913 https://orcid.org/0000-0003-1307-882X https://orcid.org/0000-0001-9249-8181 |
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