A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy
Spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) is one of nine neurodegenerative disorders that are caused by expansion of polyglutamine-encoding CAG repeats. Intracellular accumulation of abnormal proteins in these diseases, a pathological hallmark, is associated wit...
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| Veröffentlicht in: | Human molecular genetics 2016-05, Vol.25 (10), p.1979-1989 |
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| container_end_page | 1989 |
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| container_issue | 10 |
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| container_title | Human molecular genetics |
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| creator | Bott, Laura C Badders, Nisha M Chen, Ke-Lian Harmison, George G Bautista, Elaine Shih, Charles C-Y Katsuno, Masahisa Sobue, Gen Taylor, J Paul Dantuma, Nico P Fischbeck, Kenneth H Rinaldi, Carlo |
| description | Spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) is one of nine neurodegenerative disorders that are caused by expansion of polyglutamine-encoding CAG repeats. Intracellular accumulation of abnormal proteins in these diseases, a pathological hallmark, is associated with defects in protein homeostasis. Enhancement of the cellular proteostasis capacity with small molecules has therefore emerged as a promising approach to treatment. Here, we characterize a novel curcumin analog, ASC-JM17, as an activator of central pathways controlling protein folding, degradation and oxidative stress resistance. ASC-JM17 acts on Nrf1, Nrf2 and Hsf1 to increase the expression of proteasome subunits, antioxidant enzymes and molecular chaperones. We show that ASC-JM17 ameliorates toxicity of the mutant androgen receptor (AR) responsible for SBMA in cell, fly and mouse models. Knockdown of the Drosophila Nrf1 and Nrf2 ortholog cap 'n' collar isoform-C, but not Hsf1, blocks the protective effect of ASC-JM17 on mutant AR-induced eye degeneration in flies. Our observations indicate that activation of the Nrf1/Nrf2 pathway is a viable option for pharmacological intervention in SBMA and potentially other polyglutamine diseases. |
| doi_str_mv | 10.1093/hmg/ddw073 |
| format | Article |
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Intracellular accumulation of abnormal proteins in these diseases, a pathological hallmark, is associated with defects in protein homeostasis. Enhancement of the cellular proteostasis capacity with small molecules has therefore emerged as a promising approach to treatment. Here, we characterize a novel curcumin analog, ASC-JM17, as an activator of central pathways controlling protein folding, degradation and oxidative stress resistance. ASC-JM17 acts on Nrf1, Nrf2 and Hsf1 to increase the expression of proteasome subunits, antioxidant enzymes and molecular chaperones. We show that ASC-JM17 ameliorates toxicity of the mutant androgen receptor (AR) responsible for SBMA in cell, fly and mouse models. Knockdown of the Drosophila Nrf1 and Nrf2 ortholog cap 'n' collar isoform-C, but not Hsf1, blocks the protective effect of ASC-JM17 on mutant AR-induced eye degeneration in flies. Our observations indicate that activation of the Nrf1/Nrf2 pathway is a viable option for pharmacological intervention in SBMA and potentially other polyglutamine diseases.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddw073</identifier><identifier>PMID: 26962150</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Animals ; Bulbo-Spinal Atrophy, X-Linked - drug therapy ; Bulbo-Spinal Atrophy, X-Linked - genetics ; Bulbo-Spinal Atrophy, X-Linked - pathology ; Curcumin - administration & dosage ; Curcumin - analogs & derivatives ; Curcumin - chemistry ; Disease Models, Animal ; DNA-Binding Proteins - genetics ; Drosophila melanogaster - genetics ; Drosophila Proteins - genetics ; Gene Knockdown Techniques ; Heat Shock Transcription Factors ; Humans ; Mice ; Muscular Disorders, Atrophic - drug therapy ; Muscular Disorders, Atrophic - genetics ; Muscular Disorders, Atrophic - pathology ; NF-E2-Related Factor 1 - genetics ; NF-E2-Related Factor 2 - genetics ; Oxidative Stress - drug effects ; Peptides - genetics ; Proteasome Endopeptidase Complex - drug effects ; Protein Aggregation, Pathological - genetics ; Protein Folding - drug effects ; Receptors, Androgen - genetics ; Signal Transduction - drug effects ; Small Molecule Libraries - administration & dosage ; Transcription Factors - genetics ; Trinucleotide Repeat Expansion - genetics</subject><ispartof>Human molecular genetics, 2016-05, Vol.25 (10), p.1979-1989</ispartof><rights>Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.</rights><rights>Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US. 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c482t-2ad1667963437f288c3f099d5019cbb5b7a30885ddcbaa01930884b13590caa23</citedby><cites>FETCH-LOGICAL-c482t-2ad1667963437f288c3f099d5019cbb5b7a30885ddcbaa01930884b13590caa23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,550,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26962150$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:134496629$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Bott, Laura C</creatorcontrib><creatorcontrib>Badders, Nisha M</creatorcontrib><creatorcontrib>Chen, Ke-Lian</creatorcontrib><creatorcontrib>Harmison, George G</creatorcontrib><creatorcontrib>Bautista, Elaine</creatorcontrib><creatorcontrib>Shih, Charles C-Y</creatorcontrib><creatorcontrib>Katsuno, Masahisa</creatorcontrib><creatorcontrib>Sobue, Gen</creatorcontrib><creatorcontrib>Taylor, J Paul</creatorcontrib><creatorcontrib>Dantuma, Nico P</creatorcontrib><creatorcontrib>Fischbeck, Kenneth H</creatorcontrib><creatorcontrib>Rinaldi, Carlo</creatorcontrib><title>A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) is one of nine neurodegenerative disorders that are caused by expansion of polyglutamine-encoding CAG repeats. Intracellular accumulation of abnormal proteins in these diseases, a pathological hallmark, is associated with defects in protein homeostasis. Enhancement of the cellular proteostasis capacity with small molecules has therefore emerged as a promising approach to treatment. Here, we characterize a novel curcumin analog, ASC-JM17, as an activator of central pathways controlling protein folding, degradation and oxidative stress resistance. ASC-JM17 acts on Nrf1, Nrf2 and Hsf1 to increase the expression of proteasome subunits, antioxidant enzymes and molecular chaperones. We show that ASC-JM17 ameliorates toxicity of the mutant androgen receptor (AR) responsible for SBMA in cell, fly and mouse models. Knockdown of the Drosophila Nrf1 and Nrf2 ortholog cap 'n' collar isoform-C, but not Hsf1, blocks the protective effect of ASC-JM17 on mutant AR-induced eye degeneration in flies. Our observations indicate that activation of the Nrf1/Nrf2 pathway is a viable option for pharmacological intervention in SBMA and potentially other polyglutamine diseases.</description><subject>Animals</subject><subject>Bulbo-Spinal Atrophy, X-Linked - drug therapy</subject><subject>Bulbo-Spinal Atrophy, X-Linked - genetics</subject><subject>Bulbo-Spinal Atrophy, X-Linked - pathology</subject><subject>Curcumin - administration & dosage</subject><subject>Curcumin - analogs & derivatives</subject><subject>Curcumin - chemistry</subject><subject>Disease Models, Animal</subject><subject>DNA-Binding Proteins - genetics</subject><subject>Drosophila melanogaster - genetics</subject><subject>Drosophila Proteins - genetics</subject><subject>Gene Knockdown Techniques</subject><subject>Heat Shock Transcription Factors</subject><subject>Humans</subject><subject>Mice</subject><subject>Muscular Disorders, Atrophic - drug therapy</subject><subject>Muscular Disorders, Atrophic - genetics</subject><subject>Muscular Disorders, Atrophic - pathology</subject><subject>NF-E2-Related Factor 1 - genetics</subject><subject>NF-E2-Related Factor 2 - genetics</subject><subject>Oxidative Stress - drug effects</subject><subject>Peptides - genetics</subject><subject>Proteasome Endopeptidase Complex - drug effects</subject><subject>Protein Aggregation, Pathological - genetics</subject><subject>Protein Folding - drug effects</subject><subject>Receptors, Androgen - genetics</subject><subject>Signal Transduction - drug effects</subject><subject>Small Molecule Libraries - administration & dosage</subject><subject>Transcription Factors - genetics</subject><subject>Trinucleotide Repeat Expansion - genetics</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNpVUctO3DAUtaqiMkA3_QDkZVUp4EfixJtKCLUFCcGmXVs3jjPj4sSp7QDz9zjMFMHKx_eex5UOQl8oOaNE8vPNsD7vukdS8w9oRUtBCkYa_hGtiBRlISQRh-goxr-EUFHy-hM6ZEIKRiuyQv4CxwGcKwbvjJ6dwbehpxjGbgEMg072AZIPeLDJriGZiCfvtms3JxjsaHDyT1bbtMV2xHGyI7gXdTu7FrJqjtk1A0jBT5vtCTrowUXzef8eoz8_f_y-vCpu7n5dX17cFLpsWCoYdFSIWgqeD-5Z02jeEym7ilCp27Zqa-Ckaaqu0y1AHi6_sqW8kkQDMH6Mip1vfDTT3Kop2AHCVnmwaj-6z8ioigghqsz_vuPnzWA6bcYUwL2Tvd-MdqPW_mHRs6qps8HXvUHw_2YTkxps1MY5GI2fo6INy0GU1kvWtx1VBx9jMP1rDCVqaVTlRtWu0Uw-fXvYK_V_hfwZf0egJg</recordid><startdate>20160515</startdate><enddate>20160515</enddate><creator>Bott, Laura C</creator><creator>Badders, Nisha M</creator><creator>Chen, Ke-Lian</creator><creator>Harmison, George G</creator><creator>Bautista, Elaine</creator><creator>Shih, Charles C-Y</creator><creator>Katsuno, Masahisa</creator><creator>Sobue, Gen</creator><creator>Taylor, J Paul</creator><creator>Dantuma, Nico P</creator><creator>Fischbeck, Kenneth H</creator><creator>Rinaldi, Carlo</creator><general>Oxford University Press</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>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>20160515</creationdate><title>A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy</title><author>Bott, Laura C ; Badders, Nisha M ; Chen, Ke-Lian ; Harmison, George G ; Bautista, Elaine ; Shih, Charles C-Y ; Katsuno, Masahisa ; Sobue, Gen ; Taylor, J Paul ; Dantuma, Nico P ; Fischbeck, Kenneth H ; Rinaldi, Carlo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c482t-2ad1667963437f288c3f099d5019cbb5b7a30885ddcbaa01930884b13590caa23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Bulbo-Spinal Atrophy, X-Linked - drug therapy</topic><topic>Bulbo-Spinal Atrophy, X-Linked - genetics</topic><topic>Bulbo-Spinal Atrophy, X-Linked - pathology</topic><topic>Curcumin - administration & dosage</topic><topic>Curcumin - analogs & derivatives</topic><topic>Curcumin - chemistry</topic><topic>Disease Models, Animal</topic><topic>DNA-Binding Proteins - genetics</topic><topic>Drosophila melanogaster - genetics</topic><topic>Drosophila Proteins - genetics</topic><topic>Gene Knockdown Techniques</topic><topic>Heat Shock Transcription Factors</topic><topic>Humans</topic><topic>Mice</topic><topic>Muscular Disorders, Atrophic - drug therapy</topic><topic>Muscular Disorders, Atrophic - genetics</topic><topic>Muscular Disorders, Atrophic - pathology</topic><topic>NF-E2-Related Factor 1 - genetics</topic><topic>NF-E2-Related Factor 2 - genetics</topic><topic>Oxidative Stress - drug effects</topic><topic>Peptides - genetics</topic><topic>Proteasome Endopeptidase Complex - drug effects</topic><topic>Protein Aggregation, Pathological - genetics</topic><topic>Protein Folding - drug effects</topic><topic>Receptors, Androgen - genetics</topic><topic>Signal Transduction - drug effects</topic><topic>Small Molecule Libraries - administration & dosage</topic><topic>Transcription Factors - genetics</topic><topic>Trinucleotide Repeat Expansion - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bott, Laura C</creatorcontrib><creatorcontrib>Badders, Nisha M</creatorcontrib><creatorcontrib>Chen, Ke-Lian</creatorcontrib><creatorcontrib>Harmison, George G</creatorcontrib><creatorcontrib>Bautista, Elaine</creatorcontrib><creatorcontrib>Shih, Charles C-Y</creatorcontrib><creatorcontrib>Katsuno, Masahisa</creatorcontrib><creatorcontrib>Sobue, Gen</creatorcontrib><creatorcontrib>Taylor, J Paul</creatorcontrib><creatorcontrib>Dantuma, Nico P</creatorcontrib><creatorcontrib>Fischbeck, Kenneth H</creatorcontrib><creatorcontrib>Rinaldi, Carlo</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>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bott, Laura C</au><au>Badders, Nisha M</au><au>Chen, Ke-Lian</au><au>Harmison, George G</au><au>Bautista, Elaine</au><au>Shih, Charles C-Y</au><au>Katsuno, Masahisa</au><au>Sobue, Gen</au><au>Taylor, J Paul</au><au>Dantuma, Nico P</au><au>Fischbeck, Kenneth H</au><au>Rinaldi, Carlo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2016-05-15</date><risdate>2016</risdate><volume>25</volume><issue>10</issue><spage>1979</spage><epage>1989</epage><pages>1979-1989</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><abstract>Spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) is one of nine neurodegenerative disorders that are caused by expansion of polyglutamine-encoding CAG repeats. Intracellular accumulation of abnormal proteins in these diseases, a pathological hallmark, is associated with defects in protein homeostasis. Enhancement of the cellular proteostasis capacity with small molecules has therefore emerged as a promising approach to treatment. Here, we characterize a novel curcumin analog, ASC-JM17, as an activator of central pathways controlling protein folding, degradation and oxidative stress resistance. ASC-JM17 acts on Nrf1, Nrf2 and Hsf1 to increase the expression of proteasome subunits, antioxidant enzymes and molecular chaperones. We show that ASC-JM17 ameliorates toxicity of the mutant androgen receptor (AR) responsible for SBMA in cell, fly and mouse models. Knockdown of the Drosophila Nrf1 and Nrf2 ortholog cap 'n' collar isoform-C, but not Hsf1, blocks the protective effect of ASC-JM17 on mutant AR-induced eye degeneration in flies. Our observations indicate that activation of the Nrf1/Nrf2 pathway is a viable option for pharmacological intervention in SBMA and potentially other polyglutamine diseases.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>26962150</pmid><doi>10.1093/hmg/ddw073</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Bulbo-Spinal Atrophy, X-Linked - drug therapy Bulbo-Spinal Atrophy, X-Linked - genetics Bulbo-Spinal Atrophy, X-Linked - pathology Curcumin - administration & dosage Curcumin - analogs & derivatives Curcumin - chemistry Disease Models, Animal DNA-Binding Proteins - genetics Drosophila melanogaster - genetics Drosophila Proteins - genetics Gene Knockdown Techniques Heat Shock Transcription Factors Humans Mice Muscular Disorders, Atrophic - drug therapy Muscular Disorders, Atrophic - genetics Muscular Disorders, Atrophic - pathology NF-E2-Related Factor 1 - genetics NF-E2-Related Factor 2 - genetics Oxidative Stress - drug effects Peptides - genetics Proteasome Endopeptidase Complex - drug effects Protein Aggregation, Pathological - genetics Protein Folding - drug effects Receptors, Androgen - genetics Signal Transduction - drug effects Small Molecule Libraries - administration & dosage Transcription Factors - genetics Trinucleotide Repeat Expansion - genetics |
| title | A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy |
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