Identification of 12/15-lipoxygenase as a regulator of axon degeneration through high-content screening
Axon degeneration is a programed process that takes place during development, in response to neuronal injury, and as a component of neurodegenerative disease pathology, yet the molecular mechanisms that drive this process remain poorly defined. In this study, we have developed a semi-automated, 384-...
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| Veröffentlicht in: | The Journal of neuroscience 2015-02, Vol.35 (7), p.2927-2941 |
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| container_title | The Journal of neuroscience |
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| creator | Rudhard, York Sengupta Ghosh, Arundhati Lippert, Beatrix Böcker, Alexander Pedaran, Mehdi Krämer, Joachim Ngu, Hai Foreman, Oded Liu, Yichin Lewcock, Joseph W |
| description | Axon degeneration is a programed process that takes place during development, in response to neuronal injury, and as a component of neurodegenerative disease pathology, yet the molecular mechanisms that drive this process remain poorly defined. In this study, we have developed a semi-automated, 384-well format axon degeneration assay in rat dorsal root ganglion (DRG) neurons using a trophic factor withdrawal paradigm. Using this setup, we have screened a library of known drugs and bioactives to identify several previously unappreciated regulators of axon degeneration, including lipoxygenases. Multiple structurally distinct lipoxygenase inhibitors as well as mouse DRG neurons lacking expression of 12/15-lipoxygenase display protection of axons in this context. Retinal ganglion cell axons from 12/15-lipoxygenase-null mice were similarly protected from degeneration following nerve crush injury. Through additional mechanistic studies, we demonstrate that lipoxygenases act cell autonomously within neurons to regulate degeneration, and are required for mitochondrial permeabilization and caspase activation in the axon. These findings suggest that these enzymes may represent an attractive target for treatment of neuropathies and provide a potential mechanism for the neuroprotection observed in various settings following lipoxygenase inhibitor treatment. |
| doi_str_mv | 10.1523/JNEUROSCI.2936-14.2015 |
| format | Article |
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In this study, we have developed a semi-automated, 384-well format axon degeneration assay in rat dorsal root ganglion (DRG) neurons using a trophic factor withdrawal paradigm. Using this setup, we have screened a library of known drugs and bioactives to identify several previously unappreciated regulators of axon degeneration, including lipoxygenases. Multiple structurally distinct lipoxygenase inhibitors as well as mouse DRG neurons lacking expression of 12/15-lipoxygenase display protection of axons in this context. Retinal ganglion cell axons from 12/15-lipoxygenase-null mice were similarly protected from degeneration following nerve crush injury. Through additional mechanistic studies, we demonstrate that lipoxygenases act cell autonomously within neurons to regulate degeneration, and are required for mitochondrial permeabilization and caspase activation in the axon. These findings suggest that these enzymes may represent an attractive target for treatment of neuropathies and provide a potential mechanism for the neuroprotection observed in various settings following lipoxygenase inhibitor treatment.</description><identifier>ISSN: 0270-6474</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/JNEUROSCI.2936-14.2015</identifier><identifier>PMID: 25698732</identifier><language>eng</language><publisher>United States: Society for Neuroscience</publisher><subject>Algorithms ; Animals ; Arachidonate 12-Lipoxygenase - genetics ; Arachidonate 12-Lipoxygenase - metabolism ; Arachidonate 15-Lipoxygenase - genetics ; Arachidonate 15-Lipoxygenase - metabolism ; Axons - metabolism ; Axons - pathology ; Cells, Cultured ; Coculture Techniques ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Embryo, Mammalian ; Enzyme Inhibitors - pharmacology ; Female ; Ganglia, Spinal - cytology ; Gene Library ; Male ; Mice ; Mice, Transgenic ; Mitochondria - drug effects ; Mitochondria - metabolism ; Nerve Degeneration - diagnosis ; Nerve Degeneration - drug therapy ; Nerve Degeneration - enzymology ; Nerve Degeneration - etiology ; Neuroglia - cytology ; Neuroglia - drug effects ; Neuroglia - metabolism ; Neurons - cytology ; Neurons - drug effects ; Neurons - metabolism ; Optic Nerve Diseases - complications ; Rats ; Rats, Wistar ; Signal Transduction - drug effects ; Signal Transduction - genetics</subject><ispartof>The Journal of neuroscience, 2015-02, Vol.35 (7), p.2927-2941</ispartof><rights>Copyright © 2015 the authors 0270-6474/15/352927-15$15.00/0.</rights><rights>Copyright © 2015 the authors 0270-6474/15/352927-15$15.00/0 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-4a1c6bdc7eff910393e2298e6c886b7e2c4c0a8bf705e61abc7284d2fe64b49f3</citedby><cites>FETCH-LOGICAL-c447t-4a1c6bdc7eff910393e2298e6c886b7e2c4c0a8bf705e61abc7284d2fe64b49f3</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/PMC6605593/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605593/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25698732$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rudhard, York</creatorcontrib><creatorcontrib>Sengupta Ghosh, Arundhati</creatorcontrib><creatorcontrib>Lippert, Beatrix</creatorcontrib><creatorcontrib>Böcker, Alexander</creatorcontrib><creatorcontrib>Pedaran, Mehdi</creatorcontrib><creatorcontrib>Krämer, Joachim</creatorcontrib><creatorcontrib>Ngu, Hai</creatorcontrib><creatorcontrib>Foreman, Oded</creatorcontrib><creatorcontrib>Liu, Yichin</creatorcontrib><creatorcontrib>Lewcock, Joseph W</creatorcontrib><title>Identification of 12/15-lipoxygenase as a regulator of axon degeneration through high-content screening</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>Axon degeneration is a programed process that takes place during development, in response to neuronal injury, and as a component of neurodegenerative disease pathology, yet the molecular mechanisms that drive this process remain poorly defined. 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These findings suggest that these enzymes may represent an attractive target for treatment of neuropathies and provide a potential mechanism for the neuroprotection observed in various settings following lipoxygenase inhibitor treatment.</description><subject>Algorithms</subject><subject>Animals</subject><subject>Arachidonate 12-Lipoxygenase - genetics</subject><subject>Arachidonate 12-Lipoxygenase - metabolism</subject><subject>Arachidonate 15-Lipoxygenase - genetics</subject><subject>Arachidonate 15-Lipoxygenase - metabolism</subject><subject>Axons - metabolism</subject><subject>Axons - pathology</subject><subject>Cells, Cultured</subject><subject>Coculture Techniques</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Embryo, Mammalian</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Female</subject><subject>Ganglia, Spinal - cytology</subject><subject>Gene Library</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Nerve Degeneration - diagnosis</subject><subject>Nerve Degeneration - drug therapy</subject><subject>Nerve Degeneration - enzymology</subject><subject>Nerve Degeneration - etiology</subject><subject>Neuroglia - cytology</subject><subject>Neuroglia - drug effects</subject><subject>Neuroglia - metabolism</subject><subject>Neurons - cytology</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>Optic Nerve Diseases - complications</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - genetics</subject><issn>0270-6474</issn><issn>1529-2401</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1O4zAYRa0Ro6ED8wooSzYp_oudbJBQBUwRGiR-1pbjfE6M0rjYCSpvj6syFaxYeXHPvfqsg9AJwXNSUHZ28-_y6f7uYbGc04qJnPA5xaT4gWYprXLKMTlAM0wlzgWX_BD9jvEZYywxkb_QIS1EVUpGZ6hdNjCMzjqjR-eHzNuM0DNS5L1b-81bC4OOkOmY6SxAO_V69GEL6U2CG0g5hF1z7IKf2i7rXNvlxg9j2s2iCQCDG9pj9NPqPsKfj_cIPV1dPi7-5rd318vFxW1uOJdjzjUxom6MBGsrglnFgNKqBGHKUtQSqOEG67K2EhcgiK6NpCVvqAXBa15ZdoTOd7vrqV5BY9IRQfdqHdxKhzfltVNfk8F1qvWvSghcFBVLA6cfA8G_TBBHtXLRQN_rAfwUFZFUCskIxd-jokhgybBMqNihJvgYA9j9RQSrrVC1F6q2QhXhais0FU8-_2df-2-QvQNFqp-E</recordid><startdate>20150218</startdate><enddate>20150218</enddate><creator>Rudhard, York</creator><creator>Sengupta Ghosh, Arundhati</creator><creator>Lippert, Beatrix</creator><creator>Böcker, Alexander</creator><creator>Pedaran, Mehdi</creator><creator>Krämer, Joachim</creator><creator>Ngu, Hai</creator><creator>Foreman, Oded</creator><creator>Liu, Yichin</creator><creator>Lewcock, Joseph W</creator><general>Society for Neuroscience</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>7X8</scope><scope>7TK</scope><scope>5PM</scope></search><sort><creationdate>20150218</creationdate><title>Identification of 12/15-lipoxygenase as a regulator of axon degeneration through high-content screening</title><author>Rudhard, York ; Sengupta Ghosh, Arundhati ; Lippert, Beatrix ; Böcker, Alexander ; Pedaran, Mehdi ; Krämer, Joachim ; Ngu, Hai ; Foreman, Oded ; Liu, Yichin ; Lewcock, Joseph W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-4a1c6bdc7eff910393e2298e6c886b7e2c4c0a8bf705e61abc7284d2fe64b49f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Algorithms</topic><topic>Animals</topic><topic>Arachidonate 12-Lipoxygenase - genetics</topic><topic>Arachidonate 12-Lipoxygenase - metabolism</topic><topic>Arachidonate 15-Lipoxygenase - genetics</topic><topic>Arachidonate 15-Lipoxygenase - metabolism</topic><topic>Axons - metabolism</topic><topic>Axons - pathology</topic><topic>Cells, Cultured</topic><topic>Coculture Techniques</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Embryo, Mammalian</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Female</topic><topic>Ganglia, Spinal - cytology</topic><topic>Gene Library</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>Nerve Degeneration - diagnosis</topic><topic>Nerve Degeneration - drug therapy</topic><topic>Nerve Degeneration - enzymology</topic><topic>Nerve Degeneration - etiology</topic><topic>Neuroglia - cytology</topic><topic>Neuroglia - drug effects</topic><topic>Neuroglia - metabolism</topic><topic>Neurons - cytology</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>Optic Nerve Diseases - complications</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rudhard, York</creatorcontrib><creatorcontrib>Sengupta Ghosh, Arundhati</creatorcontrib><creatorcontrib>Lippert, Beatrix</creatorcontrib><creatorcontrib>Böcker, Alexander</creatorcontrib><creatorcontrib>Pedaran, Mehdi</creatorcontrib><creatorcontrib>Krämer, Joachim</creatorcontrib><creatorcontrib>Ngu, Hai</creatorcontrib><creatorcontrib>Foreman, Oded</creatorcontrib><creatorcontrib>Liu, Yichin</creatorcontrib><creatorcontrib>Lewcock, Joseph W</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rudhard, York</au><au>Sengupta Ghosh, Arundhati</au><au>Lippert, Beatrix</au><au>Böcker, Alexander</au><au>Pedaran, Mehdi</au><au>Krämer, Joachim</au><au>Ngu, Hai</au><au>Foreman, Oded</au><au>Liu, Yichin</au><au>Lewcock, Joseph W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of 12/15-lipoxygenase as a regulator of axon degeneration through high-content screening</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2015-02-18</date><risdate>2015</risdate><volume>35</volume><issue>7</issue><spage>2927</spage><epage>2941</epage><pages>2927-2941</pages><issn>0270-6474</issn><eissn>1529-2401</eissn><abstract>Axon degeneration is a programed process that takes place during development, in response to neuronal injury, and as a component of neurodegenerative disease pathology, yet the molecular mechanisms that drive this process remain poorly defined. In this study, we have developed a semi-automated, 384-well format axon degeneration assay in rat dorsal root ganglion (DRG) neurons using a trophic factor withdrawal paradigm. Using this setup, we have screened a library of known drugs and bioactives to identify several previously unappreciated regulators of axon degeneration, including lipoxygenases. Multiple structurally distinct lipoxygenase inhibitors as well as mouse DRG neurons lacking expression of 12/15-lipoxygenase display protection of axons in this context. Retinal ganglion cell axons from 12/15-lipoxygenase-null mice were similarly protected from degeneration following nerve crush injury. Through additional mechanistic studies, we demonstrate that lipoxygenases act cell autonomously within neurons to regulate degeneration, and are required for mitochondrial permeabilization and caspase activation in the axon. These findings suggest that these enzymes may represent an attractive target for treatment of neuropathies and provide a potential mechanism for the neuroprotection observed in various settings following lipoxygenase inhibitor treatment.</abstract><cop>United States</cop><pub>Society for Neuroscience</pub><pmid>25698732</pmid><doi>10.1523/JNEUROSCI.2936-14.2015</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Algorithms Animals Arachidonate 12-Lipoxygenase - genetics Arachidonate 12-Lipoxygenase - metabolism Arachidonate 15-Lipoxygenase - genetics Arachidonate 15-Lipoxygenase - metabolism Axons - metabolism Axons - pathology Cells, Cultured Coculture Techniques Disease Models, Animal Dose-Response Relationship, Drug Embryo, Mammalian Enzyme Inhibitors - pharmacology Female Ganglia, Spinal - cytology Gene Library Male Mice Mice, Transgenic Mitochondria - drug effects Mitochondria - metabolism Nerve Degeneration - diagnosis Nerve Degeneration - drug therapy Nerve Degeneration - enzymology Nerve Degeneration - etiology Neuroglia - cytology Neuroglia - drug effects Neuroglia - metabolism Neurons - cytology Neurons - drug effects Neurons - metabolism Optic Nerve Diseases - complications Rats Rats, Wistar Signal Transduction - drug effects Signal Transduction - genetics |
| title | Identification of 12/15-lipoxygenase as a regulator of axon degeneration through high-content screening |
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