The indole compound NC009-1 inhibits aggregation and promotes neurite outgrowth through enhancement of HSPB1 in SCA17 cells and ameliorates the behavioral deficits in SCA17 mice
•NC009-1 inhibits polyQ aggregation and polyQ-induced ROS in TBP/Q79 293 cells.•NC009-1 reduces aggregation & promotes neurite outgrowth in TBP/Q79 SH-SY5Y cells.•NC009-1 enhances HSPB1 to ameliorate BID-CYCS-CASP3 pathway and outgrowth defect.•NC009-1 reduces aggregation & ameliorates behav...
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| Veröffentlicht in: | Neurotoxicology (Park Forest South) 2018-07, Vol.67, p.259-269 |
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| creator | Chen, Chiung-Mei Chen, Wan-Ling Hung, Chen-Ting Lin, Te-Hsien Chao, Chih-Ying Lin, Chih-Hsin Wu, Yih-Ru Chang, Kuo-Hsuan Yao, Ching-Fa Lee-Chen, Guey-Jen Su, Ming-Tsan Hsieh-Li, Hsiu Mei |
| description | •NC009-1 inhibits polyQ aggregation and polyQ-induced ROS in TBP/Q79 293 cells.•NC009-1 reduces aggregation & promotes neurite outgrowth in TBP/Q79 SH-SY5Y cells.•NC009-1 enhances HSPB1 to ameliorate BID-CYCS-CASP3 pathway and outgrowth defect.•NC009-1 reduces aggregation & ameliorates behavioral deficits in TBP/Q109 transgenic mice.
Spinocerebellar ataxia type 17 (SCA17) is caused by the expansion of translated CAG repeat in the TATA box binding protein (TBP) gene encoding a long polyglutamine (polyQ) tract in the TBP protein, which leads to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On cells with inducible SCA17 TBP/Q79-GFP expression to test five in-house NC009 indole compounds for neuroprotection. We found that both aggregation and polyQ-induced reactive oxygen species can be significantly prohibited by the tested NC009 compounds in Tet-On TBP/Q79 293 cells. Among the five indole compounds, NC009-1 up-regulated expression of heat shock protein family B (small) member 1 (HSPB1) chaperone to reduce polyQ aggregation and promote neurite outgrowth in neuronal differentiated TBP/Q79 SH-SY5Y cells. The increased HSPB1 thus ameliorated the increased BH3 interacting domain death agonist (BID), cytochrome c (CYCS) release, and caspase 3 (CASP3) activation which result in apoptosis. Knock down of HSPB1 attenuated the effects of NC009-1 on TBP/Q79 SH-SY5Y cells, suggesting that HSPB1 might be one of the major pathways involved for NC009-1 effects. NC009-1 further reduced polyQ aggregation in Purkinje cells and ameliorated behavioral deficits in SCA17 TBP/Q109 transgenic mice. Our results suggest that NC009-1 has a neuroprotective effect on SCA17 cell and mouse models to support its therapeutic potential in SCA17 treatment. |
| doi_str_mv | 10.1016/j.neuro.2018.06.009 |
| format | Article |
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Spinocerebellar ataxia type 17 (SCA17) is caused by the expansion of translated CAG repeat in the TATA box binding protein (TBP) gene encoding a long polyglutamine (polyQ) tract in the TBP protein, which leads to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On cells with inducible SCA17 TBP/Q79-GFP expression to test five in-house NC009 indole compounds for neuroprotection. We found that both aggregation and polyQ-induced reactive oxygen species can be significantly prohibited by the tested NC009 compounds in Tet-On TBP/Q79 293 cells. Among the five indole compounds, NC009-1 up-regulated expression of heat shock protein family B (small) member 1 (HSPB1) chaperone to reduce polyQ aggregation and promote neurite outgrowth in neuronal differentiated TBP/Q79 SH-SY5Y cells. The increased HSPB1 thus ameliorated the increased BH3 interacting domain death agonist (BID), cytochrome c (CYCS) release, and caspase 3 (CASP3) activation which result in apoptosis. Knock down of HSPB1 attenuated the effects of NC009-1 on TBP/Q79 SH-SY5Y cells, suggesting that HSPB1 might be one of the major pathways involved for NC009-1 effects. NC009-1 further reduced polyQ aggregation in Purkinje cells and ameliorated behavioral deficits in SCA17 TBP/Q109 transgenic mice. Our results suggest that NC009-1 has a neuroprotective effect on SCA17 cell and mouse models to support its therapeutic potential in SCA17 treatment.</description><identifier>ISSN: 0161-813X</identifier><identifier>EISSN: 1872-9711</identifier><identifier>DOI: 10.1016/j.neuro.2018.06.009</identifier><identifier>PMID: 29936316</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Agglomeration ; Animal models ; Animals ; Apoptosis ; Ataxia ; Axonogenesis ; Caspase ; Caspase-3 ; Cell culture ; Cell death ; Cell Line, Tumor ; Chaperones ; Cytochrome ; Cytochrome c ; Cytochromes ; Dose-Response Relationship, Drug ; Heat shock proteins ; Heat-Shock Proteins - agonists ; Heat-Shock Proteins - metabolism ; HSPB1 ; Humans ; Indole compound ; Indoles ; Indoles - chemistry ; Indoles - pharmacology ; Indoles - therapeutic use ; Mental Disorders - drug therapy ; Mental Disorders - metabolism ; Mice ; Mice, Transgenic ; Neoplasm Proteins - agonists ; Neoplasm Proteins - metabolism ; Neuronal Outgrowth - drug effects ; Neuronal Outgrowth - physiology ; Neuroprotection ; Polyglutamine ; PolyQ aggregation ; Protein interaction ; Purkinje cells ; Reactive oxygen species ; Rodents ; Spinocerebellar ataxia type 17 ; Tata box ; TATA box binding protein ; TATA-Box Binding Protein - genetics ; TATA-Box Binding Protein - metabolism ; Therapeutics ; Transgenic mice ; Trinucleotide repeat diseases ; Trinucleotide repeats</subject><ispartof>Neurotoxicology (Park Forest South), 2018-07, Vol.67, p.259-269</ispartof><rights>2018 Elsevier B.V.</rights><rights>Copyright © 2018 Elsevier B.V. All rights reserved.</rights><rights>Copyright Elsevier BV Jul 2018</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c387t-431153d5277e2dfa549cc8393fe6a42a33420c09e7f56eda28b846516846dc833</citedby><cites>FETCH-LOGICAL-c387t-431153d5277e2dfa549cc8393fe6a42a33420c09e7f56eda28b846516846dc833</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.neuro.2018.06.009$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29936316$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Chiung-Mei</creatorcontrib><creatorcontrib>Chen, Wan-Ling</creatorcontrib><creatorcontrib>Hung, Chen-Ting</creatorcontrib><creatorcontrib>Lin, Te-Hsien</creatorcontrib><creatorcontrib>Chao, Chih-Ying</creatorcontrib><creatorcontrib>Lin, Chih-Hsin</creatorcontrib><creatorcontrib>Wu, Yih-Ru</creatorcontrib><creatorcontrib>Chang, Kuo-Hsuan</creatorcontrib><creatorcontrib>Yao, Ching-Fa</creatorcontrib><creatorcontrib>Lee-Chen, Guey-Jen</creatorcontrib><creatorcontrib>Su, Ming-Tsan</creatorcontrib><creatorcontrib>Hsieh-Li, Hsiu Mei</creatorcontrib><title>The indole compound NC009-1 inhibits aggregation and promotes neurite outgrowth through enhancement of HSPB1 in SCA17 cells and ameliorates the behavioral deficits in SCA17 mice</title><title>Neurotoxicology (Park Forest South)</title><addtitle>Neurotoxicology</addtitle><description>•NC009-1 inhibits polyQ aggregation and polyQ-induced ROS in TBP/Q79 293 cells.•NC009-1 reduces aggregation & promotes neurite outgrowth in TBP/Q79 SH-SY5Y cells.•NC009-1 enhances HSPB1 to ameliorate BID-CYCS-CASP3 pathway and outgrowth defect.•NC009-1 reduces aggregation & ameliorates behavioral deficits in TBP/Q109 transgenic mice.
Spinocerebellar ataxia type 17 (SCA17) is caused by the expansion of translated CAG repeat in the TATA box binding protein (TBP) gene encoding a long polyglutamine (polyQ) tract in the TBP protein, which leads to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On cells with inducible SCA17 TBP/Q79-GFP expression to test five in-house NC009 indole compounds for neuroprotection. We found that both aggregation and polyQ-induced reactive oxygen species can be significantly prohibited by the tested NC009 compounds in Tet-On TBP/Q79 293 cells. Among the five indole compounds, NC009-1 up-regulated expression of heat shock protein family B (small) member 1 (HSPB1) chaperone to reduce polyQ aggregation and promote neurite outgrowth in neuronal differentiated TBP/Q79 SH-SY5Y cells. The increased HSPB1 thus ameliorated the increased BH3 interacting domain death agonist (BID), cytochrome c (CYCS) release, and caspase 3 (CASP3) activation which result in apoptosis. Knock down of HSPB1 attenuated the effects of NC009-1 on TBP/Q79 SH-SY5Y cells, suggesting that HSPB1 might be one of the major pathways involved for NC009-1 effects. NC009-1 further reduced polyQ aggregation in Purkinje cells and ameliorated behavioral deficits in SCA17 TBP/Q109 transgenic mice. Our results suggest that NC009-1 has a neuroprotective effect on SCA17 cell and mouse models to support its therapeutic potential in SCA17 treatment.</description><subject>Agglomeration</subject><subject>Animal models</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Ataxia</subject><subject>Axonogenesis</subject><subject>Caspase</subject><subject>Caspase-3</subject><subject>Cell culture</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Chaperones</subject><subject>Cytochrome</subject><subject>Cytochrome c</subject><subject>Cytochromes</subject><subject>Dose-Response Relationship, Drug</subject><subject>Heat shock proteins</subject><subject>Heat-Shock Proteins - agonists</subject><subject>Heat-Shock Proteins - metabolism</subject><subject>HSPB1</subject><subject>Humans</subject><subject>Indole compound</subject><subject>Indoles</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Indoles - therapeutic use</subject><subject>Mental Disorders - drug therapy</subject><subject>Mental Disorders - metabolism</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Neoplasm Proteins - agonists</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Neuronal Outgrowth - drug effects</subject><subject>Neuronal Outgrowth - physiology</subject><subject>Neuroprotection</subject><subject>Polyglutamine</subject><subject>PolyQ aggregation</subject><subject>Protein interaction</subject><subject>Purkinje cells</subject><subject>Reactive oxygen species</subject><subject>Rodents</subject><subject>Spinocerebellar ataxia type 17</subject><subject>Tata box</subject><subject>TATA box binding protein</subject><subject>TATA-Box Binding Protein - genetics</subject><subject>TATA-Box Binding Protein - metabolism</subject><subject>Therapeutics</subject><subject>Transgenic mice</subject><subject>Trinucleotide repeat diseases</subject><subject>Trinucleotide repeats</subject><issn>0161-813X</issn><issn>1872-9711</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc9u1DAQxi0EokvhCZCQJS5cEvwnceIDh3ZFKVIFSC0SN8trTxKvknixnSIeq2-I0y09cOBiS6PffPPNfAi9pqSkhIr3-3KGJfiSEdqWRJSEyCdoQ9uGFbKh9CnaZIoWLeU_TtCLGPeE0LoR8jk6YVJywanYoLubAbCbrR8BGz8d_DJb_GWbtQqa64PbuRSx7vsAvU7Oz1hn4BD85BNEvDpwCbBfUh_8rzTgNAS_9AOGedCzgQnmhH2HL6-_na-C-Hp7RhtsYBzjvZSeYHQ-6FUtZS87GPTtWhixhc6Zdfxj2-QMvETPOj1GePXwn6LvFx9vtpfF1ddPn7dnV4XhbZOKilNac1uzpgFmO11X0piWS96B0BXTnFeMGCKh6WoBVrN211aipiK_NoP8FL076uZlfy4Qk5pcXH3rGfwSFSO1JFXFRZvRt_-ge7-EObtTjFLGKJGizhQ_Uib4GAN06hDcpMNvRYlaE1V7dZ-oWhNVRKicQu5686C97Cawjz1_I8zAhyMA-Ri3DoKKxkE-vXUBTFLWu_8O-ANAOrLg</recordid><startdate>201807</startdate><enddate>201807</enddate><creator>Chen, Chiung-Mei</creator><creator>Chen, Wan-Ling</creator><creator>Hung, Chen-Ting</creator><creator>Lin, Te-Hsien</creator><creator>Chao, Chih-Ying</creator><creator>Lin, Chih-Hsin</creator><creator>Wu, Yih-Ru</creator><creator>Chang, Kuo-Hsuan</creator><creator>Yao, Ching-Fa</creator><creator>Lee-Chen, Guey-Jen</creator><creator>Su, Ming-Tsan</creator><creator>Hsieh-Li, Hsiu Mei</creator><general>Elsevier B.V</general><general>Elsevier BV</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>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>7X8</scope></search><sort><creationdate>201807</creationdate><title>The indole compound NC009-1 inhibits aggregation and promotes neurite outgrowth through enhancement of HSPB1 in SCA17 cells and ameliorates the behavioral deficits in SCA17 mice</title><author>Chen, Chiung-Mei ; Chen, Wan-Ling ; Hung, Chen-Ting ; Lin, Te-Hsien ; Chao, Chih-Ying ; Lin, Chih-Hsin ; Wu, Yih-Ru ; Chang, Kuo-Hsuan ; Yao, Ching-Fa ; Lee-Chen, Guey-Jen ; Su, Ming-Tsan ; Hsieh-Li, Hsiu Mei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-431153d5277e2dfa549cc8393fe6a42a33420c09e7f56eda28b846516846dc833</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Agglomeration</topic><topic>Animal models</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Ataxia</topic><topic>Axonogenesis</topic><topic>Caspase</topic><topic>Caspase-3</topic><topic>Cell culture</topic><topic>Cell death</topic><topic>Cell Line, Tumor</topic><topic>Chaperones</topic><topic>Cytochrome</topic><topic>Cytochrome c</topic><topic>Cytochromes</topic><topic>Dose-Response Relationship, Drug</topic><topic>Heat shock proteins</topic><topic>Heat-Shock Proteins - agonists</topic><topic>Heat-Shock Proteins - metabolism</topic><topic>HSPB1</topic><topic>Humans</topic><topic>Indole compound</topic><topic>Indoles</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>Indoles - therapeutic use</topic><topic>Mental Disorders - drug therapy</topic><topic>Mental Disorders - metabolism</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Neoplasm Proteins - agonists</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Neuronal Outgrowth - drug effects</topic><topic>Neuronal Outgrowth - physiology</topic><topic>Neuroprotection</topic><topic>Polyglutamine</topic><topic>PolyQ aggregation</topic><topic>Protein interaction</topic><topic>Purkinje cells</topic><topic>Reactive oxygen species</topic><topic>Rodents</topic><topic>Spinocerebellar ataxia type 17</topic><topic>Tata box</topic><topic>TATA box binding protein</topic><topic>TATA-Box Binding Protein - genetics</topic><topic>TATA-Box Binding Protein - metabolism</topic><topic>Therapeutics</topic><topic>Transgenic mice</topic><topic>Trinucleotide repeat diseases</topic><topic>Trinucleotide repeats</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Chiung-Mei</creatorcontrib><creatorcontrib>Chen, Wan-Ling</creatorcontrib><creatorcontrib>Hung, Chen-Ting</creatorcontrib><creatorcontrib>Lin, Te-Hsien</creatorcontrib><creatorcontrib>Chao, Chih-Ying</creatorcontrib><creatorcontrib>Lin, Chih-Hsin</creatorcontrib><creatorcontrib>Wu, Yih-Ru</creatorcontrib><creatorcontrib>Chang, Kuo-Hsuan</creatorcontrib><creatorcontrib>Yao, Ching-Fa</creatorcontrib><creatorcontrib>Lee-Chen, Guey-Jen</creatorcontrib><creatorcontrib>Su, Ming-Tsan</creatorcontrib><creatorcontrib>Hsieh-Li, Hsiu Mei</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><jtitle>Neurotoxicology (Park Forest South)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Chiung-Mei</au><au>Chen, Wan-Ling</au><au>Hung, Chen-Ting</au><au>Lin, Te-Hsien</au><au>Chao, Chih-Ying</au><au>Lin, Chih-Hsin</au><au>Wu, Yih-Ru</au><au>Chang, Kuo-Hsuan</au><au>Yao, Ching-Fa</au><au>Lee-Chen, Guey-Jen</au><au>Su, Ming-Tsan</au><au>Hsieh-Li, Hsiu Mei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The indole compound NC009-1 inhibits aggregation and promotes neurite outgrowth through enhancement of HSPB1 in SCA17 cells and ameliorates the behavioral deficits in SCA17 mice</atitle><jtitle>Neurotoxicology (Park Forest South)</jtitle><addtitle>Neurotoxicology</addtitle><date>2018-07</date><risdate>2018</risdate><volume>67</volume><spage>259</spage><epage>269</epage><pages>259-269</pages><issn>0161-813X</issn><eissn>1872-9711</eissn><abstract>•NC009-1 inhibits polyQ aggregation and polyQ-induced ROS in TBP/Q79 293 cells.•NC009-1 reduces aggregation & promotes neurite outgrowth in TBP/Q79 SH-SY5Y cells.•NC009-1 enhances HSPB1 to ameliorate BID-CYCS-CASP3 pathway and outgrowth defect.•NC009-1 reduces aggregation & ameliorates behavioral deficits in TBP/Q109 transgenic mice.
Spinocerebellar ataxia type 17 (SCA17) is caused by the expansion of translated CAG repeat in the TATA box binding protein (TBP) gene encoding a long polyglutamine (polyQ) tract in the TBP protein, which leads to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On cells with inducible SCA17 TBP/Q79-GFP expression to test five in-house NC009 indole compounds for neuroprotection. We found that both aggregation and polyQ-induced reactive oxygen species can be significantly prohibited by the tested NC009 compounds in Tet-On TBP/Q79 293 cells. Among the five indole compounds, NC009-1 up-regulated expression of heat shock protein family B (small) member 1 (HSPB1) chaperone to reduce polyQ aggregation and promote neurite outgrowth in neuronal differentiated TBP/Q79 SH-SY5Y cells. The increased HSPB1 thus ameliorated the increased BH3 interacting domain death agonist (BID), cytochrome c (CYCS) release, and caspase 3 (CASP3) activation which result in apoptosis. Knock down of HSPB1 attenuated the effects of NC009-1 on TBP/Q79 SH-SY5Y cells, suggesting that HSPB1 might be one of the major pathways involved for NC009-1 effects. NC009-1 further reduced polyQ aggregation in Purkinje cells and ameliorated behavioral deficits in SCA17 TBP/Q109 transgenic mice. Our results suggest that NC009-1 has a neuroprotective effect on SCA17 cell and mouse models to support its therapeutic potential in SCA17 treatment.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>29936316</pmid><doi>10.1016/j.neuro.2018.06.009</doi><tpages>11</tpages></addata></record> |
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| subjects | Agglomeration Animal models Animals Apoptosis Ataxia Axonogenesis Caspase Caspase-3 Cell culture Cell death Cell Line, Tumor Chaperones Cytochrome Cytochrome c Cytochromes Dose-Response Relationship, Drug Heat shock proteins Heat-Shock Proteins - agonists Heat-Shock Proteins - metabolism HSPB1 Humans Indole compound Indoles Indoles - chemistry Indoles - pharmacology Indoles - therapeutic use Mental Disorders - drug therapy Mental Disorders - metabolism Mice Mice, Transgenic Neoplasm Proteins - agonists Neoplasm Proteins - metabolism Neuronal Outgrowth - drug effects Neuronal Outgrowth - physiology Neuroprotection Polyglutamine PolyQ aggregation Protein interaction Purkinje cells Reactive oxygen species Rodents Spinocerebellar ataxia type 17 Tata box TATA box binding protein TATA-Box Binding Protein - genetics TATA-Box Binding Protein - metabolism Therapeutics Transgenic mice Trinucleotide repeat diseases Trinucleotide repeats |
| title | The indole compound NC009-1 inhibits aggregation and promotes neurite outgrowth through enhancement of HSPB1 in SCA17 cells and ameliorates the behavioral deficits in SCA17 mice |
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