Inhibition of prolyl oligopeptidase increases the survival of alpha-synuclein overexpressing cells after rotenone exposure by reducing alpha-synuclein oligomers
•Rotenone induced α-synuclein (aSyn) aggregation in [A53T]aSyn overexpressing cells.•Prolyl oligopeptidase (PREP) inhibition reduced the levels of aSyn oligomers.•PREP inhibition decreased ROS production by reducing aSyn oligomers.•These effects of PREP inhibition led to increased cell survival. α-S...
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| Veröffentlicht in: | Neuroscience letters 2014-11, Vol.583, p.37-42 |
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| creator | Dokleja, Lana Hannula, Mirva J. Myöhänen, Timo T. |
| description | •Rotenone induced α-synuclein (aSyn) aggregation in [A53T]aSyn overexpressing cells.•Prolyl oligopeptidase (PREP) inhibition reduced the levels of aSyn oligomers.•PREP inhibition decreased ROS production by reducing aSyn oligomers.•These effects of PREP inhibition led to increased cell survival.
α-Synuclein (aSyn) aggregation, mitochondrial dysfunction and oxidative damage has been shown to be related to the death of dopaminergic neurons in Parkinson's disease (PD). Prolyl oligopeptidase (PREP) is proposed to increase aSyn aggregation, and PREP inhibition has been shown to inhibit the aggregation process in vitro and in vivo. In this study, we investigated the effects of a specific PREP inhibitor, KYP-2047, on rotenone induced aSyn aggregation and increased the production of reactive oxygen species (ROS) in cells overexpressing A53T mutation of aSyn. Rotenone, a mitochondrial toxin that induces oxidative damage and aSyn aggregation, associated with PD pathology, was selected as a model for this study. The results showed that rotenone induced the formation of high-molecular-weight aSyn oligomers, and this was countered by simultaneous incubation with KYP-2047. Inhibition of PREP also decreased the production of ROS in [A53T]aSyn overexpressing cells, leading to improved cell viability. |
| doi_str_mv | 10.1016/j.neulet.2014.09.026 |
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α-Synuclein (aSyn) aggregation, mitochondrial dysfunction and oxidative damage has been shown to be related to the death of dopaminergic neurons in Parkinson's disease (PD). Prolyl oligopeptidase (PREP) is proposed to increase aSyn aggregation, and PREP inhibition has been shown to inhibit the aggregation process in vitro and in vivo. In this study, we investigated the effects of a specific PREP inhibitor, KYP-2047, on rotenone induced aSyn aggregation and increased the production of reactive oxygen species (ROS) in cells overexpressing A53T mutation of aSyn. Rotenone, a mitochondrial toxin that induces oxidative damage and aSyn aggregation, associated with PD pathology, was selected as a model for this study. The results showed that rotenone induced the formation of high-molecular-weight aSyn oligomers, and this was countered by simultaneous incubation with KYP-2047. Inhibition of PREP also decreased the production of ROS in [A53T]aSyn overexpressing cells, leading to improved cell viability.</description><identifier>ISSN: 0304-3940</identifier><identifier>EISSN: 1872-7972</identifier><identifier>DOI: 10.1016/j.neulet.2014.09.026</identifier><identifier>PMID: 25240592</identifier><language>eng</language><publisher>Ireland: Elsevier Ireland Ltd</publisher><subject>alpha-Synuclein - genetics ; alpha-Synuclein - metabolism ; Autophagy ; Cell Line, Tumor ; Humans ; Mitochondria - metabolism ; Mutation ; Parkinson's disease ; Proline - analogs & derivatives ; Proline - pharmacology ; Protein Aggregates ; Protein misfolding ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Rotenone - toxicity ; Serine Endopeptidases - metabolism ; Serine protease ; Serine Proteinase Inhibitors - pharmacology ; Solubility</subject><ispartof>Neuroscience letters, 2014-11, Vol.583, p.37-42</ispartof><rights>2014 Elsevier Ireland Ltd</rights><rights>Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c461t-f532a06ef599050de462f84a366b4c61c0e0d277f2863cd1cf57b4da37f12b33</citedby><cites>FETCH-LOGICAL-c461t-f532a06ef599050de462f84a366b4c61c0e0d277f2863cd1cf57b4da37f12b33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0304394014007630$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25240592$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dokleja, Lana</creatorcontrib><creatorcontrib>Hannula, Mirva J.</creatorcontrib><creatorcontrib>Myöhänen, Timo T.</creatorcontrib><title>Inhibition of prolyl oligopeptidase increases the survival of alpha-synuclein overexpressing cells after rotenone exposure by reducing alpha-synuclein oligomers</title><title>Neuroscience letters</title><addtitle>Neurosci Lett</addtitle><description>•Rotenone induced α-synuclein (aSyn) aggregation in [A53T]aSyn overexpressing cells.•Prolyl oligopeptidase (PREP) inhibition reduced the levels of aSyn oligomers.•PREP inhibition decreased ROS production by reducing aSyn oligomers.•These effects of PREP inhibition led to increased cell survival.
α-Synuclein (aSyn) aggregation, mitochondrial dysfunction and oxidative damage has been shown to be related to the death of dopaminergic neurons in Parkinson's disease (PD). Prolyl oligopeptidase (PREP) is proposed to increase aSyn aggregation, and PREP inhibition has been shown to inhibit the aggregation process in vitro and in vivo. In this study, we investigated the effects of a specific PREP inhibitor, KYP-2047, on rotenone induced aSyn aggregation and increased the production of reactive oxygen species (ROS) in cells overexpressing A53T mutation of aSyn. Rotenone, a mitochondrial toxin that induces oxidative damage and aSyn aggregation, associated with PD pathology, was selected as a model for this study. The results showed that rotenone induced the formation of high-molecular-weight aSyn oligomers, and this was countered by simultaneous incubation with KYP-2047. Inhibition of PREP also decreased the production of ROS in [A53T]aSyn overexpressing cells, leading to improved cell viability.</description><subject>alpha-Synuclein - genetics</subject><subject>alpha-Synuclein - metabolism</subject><subject>Autophagy</subject><subject>Cell Line, Tumor</subject><subject>Humans</subject><subject>Mitochondria - metabolism</subject><subject>Mutation</subject><subject>Parkinson's disease</subject><subject>Proline - analogs & derivatives</subject><subject>Proline - pharmacology</subject><subject>Protein Aggregates</subject><subject>Protein misfolding</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Rotenone - toxicity</subject><subject>Serine Endopeptidases - metabolism</subject><subject>Serine protease</subject><subject>Serine Proteinase Inhibitors - pharmacology</subject><subject>Solubility</subject><issn>0304-3940</issn><issn>1872-7972</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc-KFDEQh4Mo7rj6BiI5eumx8qfT0xdBllUXFrzsPaTTlZ0MmaRNugfnbXxU08zqRRBPKchXvyrqI-Qtgy0Dpj4cthGXgPOWA5Nb6LfA1TOyYbuON13f8edkAwJkI3oJV-RVKQcAaFkrX5Ir3nIJbc835Odd3PvBzz5FmhydcgrnQFPwj2nCafajKUh9tBlrUei8R1qWfPInE1behGlvmnKOiw3oa8QJM_6YMpbi4yO1GEKhxs2YaU4zxhSR1v9UM5AOZ5pxXOxK_hW0bnDEXF6TF86Egm-e3mvy8Pn24eZrc__ty93Np_vGSsXmxrWCG1Do2r6HFkaUirudNEKpQVrFLCCMvOsc3ylhR2Zd2w1yNKJzjA9CXJP3l9h6ge8LllkffVnXNxHTUjRTogUhO6n-A-V9r9ROdhWVF9TmVEpGp6fsjyafNQO9WtQHfbGoV4sael0t1rZ3TxOW4Yjjn6bf2irw8QJgvcjJY9bFeowWR5_RznpM_t8TfgGLk7UC</recordid><startdate>20141107</startdate><enddate>20141107</enddate><creator>Dokleja, Lana</creator><creator>Hannula, Mirva J.</creator><creator>Myöhänen, Timo T.</creator><general>Elsevier Ireland Ltd</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></search><sort><creationdate>20141107</creationdate><title>Inhibition of prolyl oligopeptidase increases the survival of alpha-synuclein overexpressing cells after rotenone exposure by reducing alpha-synuclein oligomers</title><author>Dokleja, Lana ; Hannula, Mirva J. ; Myöhänen, Timo T.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c461t-f532a06ef599050de462f84a366b4c61c0e0d277f2863cd1cf57b4da37f12b33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>alpha-Synuclein - genetics</topic><topic>alpha-Synuclein - metabolism</topic><topic>Autophagy</topic><topic>Cell Line, Tumor</topic><topic>Humans</topic><topic>Mitochondria - metabolism</topic><topic>Mutation</topic><topic>Parkinson's disease</topic><topic>Proline - analogs & derivatives</topic><topic>Proline - pharmacology</topic><topic>Protein Aggregates</topic><topic>Protein misfolding</topic><topic>Reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Rotenone - toxicity</topic><topic>Serine Endopeptidases - metabolism</topic><topic>Serine protease</topic><topic>Serine Proteinase Inhibitors - pharmacology</topic><topic>Solubility</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dokleja, Lana</creatorcontrib><creatorcontrib>Hannula, Mirva J.</creatorcontrib><creatorcontrib>Myöhänen, Timo T.</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><jtitle>Neuroscience letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dokleja, Lana</au><au>Hannula, Mirva J.</au><au>Myöhänen, Timo T.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of prolyl oligopeptidase increases the survival of alpha-synuclein overexpressing cells after rotenone exposure by reducing alpha-synuclein oligomers</atitle><jtitle>Neuroscience letters</jtitle><addtitle>Neurosci Lett</addtitle><date>2014-11-07</date><risdate>2014</risdate><volume>583</volume><spage>37</spage><epage>42</epage><pages>37-42</pages><issn>0304-3940</issn><eissn>1872-7972</eissn><abstract>•Rotenone induced α-synuclein (aSyn) aggregation in [A53T]aSyn overexpressing cells.•Prolyl oligopeptidase (PREP) inhibition reduced the levels of aSyn oligomers.•PREP inhibition decreased ROS production by reducing aSyn oligomers.•These effects of PREP inhibition led to increased cell survival.
α-Synuclein (aSyn) aggregation, mitochondrial dysfunction and oxidative damage has been shown to be related to the death of dopaminergic neurons in Parkinson's disease (PD). Prolyl oligopeptidase (PREP) is proposed to increase aSyn aggregation, and PREP inhibition has been shown to inhibit the aggregation process in vitro and in vivo. In this study, we investigated the effects of a specific PREP inhibitor, KYP-2047, on rotenone induced aSyn aggregation and increased the production of reactive oxygen species (ROS) in cells overexpressing A53T mutation of aSyn. Rotenone, a mitochondrial toxin that induces oxidative damage and aSyn aggregation, associated with PD pathology, was selected as a model for this study. The results showed that rotenone induced the formation of high-molecular-weight aSyn oligomers, and this was countered by simultaneous incubation with KYP-2047. Inhibition of PREP also decreased the production of ROS in [A53T]aSyn overexpressing cells, leading to improved cell viability.</abstract><cop>Ireland</cop><pub>Elsevier Ireland Ltd</pub><pmid>25240592</pmid><doi>10.1016/j.neulet.2014.09.026</doi><tpages>6</tpages></addata></record> |
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| subjects | alpha-Synuclein - genetics alpha-Synuclein - metabolism Autophagy Cell Line, Tumor Humans Mitochondria - metabolism Mutation Parkinson's disease Proline - analogs & derivatives Proline - pharmacology Protein Aggregates Protein misfolding Reactive oxygen species Reactive Oxygen Species - metabolism Rotenone - toxicity Serine Endopeptidases - metabolism Serine protease Serine Proteinase Inhibitors - pharmacology Solubility |
| title | Inhibition of prolyl oligopeptidase increases the survival of alpha-synuclein overexpressing cells after rotenone exposure by reducing alpha-synuclein oligomers |
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