A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD

One drug, two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide t...
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Autor*in:	Qian Zhang [verfasserIn] Ying An [verfasserIn] Zhefan Stephen Chen [verfasserIn] Alex Chun Koon [verfasserIn] Kwok-Fai Lau [verfasserIn] Jacky Chi Ki Ngo [verfasserIn] Ho Yin Edwin Chan [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Übergeordnetes Werk:	In: Molecular Therapy: Nucleic Acids - Elsevier, 2013, 16(2019), Seite 172-185
Übergeordnetes Werk:	volume:16 ; year:2019 ; pages:172-185

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1016/j.omtn.2019.02.015

Katalog-ID:	DOAJ019339992

Internformat


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520			\|a One drug, two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV, TAT-BIND reduces cell death, formation of GGGGCC RNA foci, and levels of poly-GR, poly-GA, and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein, restores rRNA maturation, and inhibits mislocalization of nucleolin and B23, which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD, TAT-BIND suppresses retinal degeneration, rescues climbing ability, and extends the lifespan of flies. In contrast, TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)100-expressing flies, which generate only poly-GR protein toxicity, indicating BIND ameliorates toxicity in C9ALS-FTD models via a r(GGGGCC)exp-dependent inhibitory mechanism. Our findings demonstrated that, apart from being a potential therapeutic for polyQ diseases, BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration, highlighting its potential application in C9ALS-FTD treatment. Keywords: G4C2, amyotrophic lateral sclerosis, frontotemporal dementia, cell-penetrating peptide, peptide inhibitor, C9ORF72
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publishDate	2019
allfields	10.1016/j.omtn.2019.02.015 doi (DE-627)DOAJ019339992 (DE-599)DOAJ93a3c017448d49dfb54ad5fc338c760b DE-627 ger DE-627 rakwb eng RM1-950 Qian Zhang verfasserin aut A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier One drug, two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV, TAT-BIND reduces cell death, formation of GGGGCC RNA foci, and levels of poly-GR, poly-GA, and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein, restores rRNA maturation, and inhibits mislocalization of nucleolin and B23, which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD, TAT-BIND suppresses retinal degeneration, rescues climbing ability, and extends the lifespan of flies. In contrast, TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)100-expressing flies, which generate only poly-GR protein toxicity, indicating BIND ameliorates toxicity in C9ALS-FTD models via a r(GGGGCC)exp-dependent inhibitory mechanism. Our findings demonstrated that, apart from being a potential therapeutic for polyQ diseases, BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration, highlighting its potential application in C9ALS-FTD treatment. Keywords: G4C2, amyotrophic lateral sclerosis, frontotemporal dementia, cell-penetrating peptide, peptide inhibitor, C9ORF72 Therapeutics. Pharmacology Ying An verfasserin aut Zhefan Stephen Chen verfasserin aut Alex Chun Koon verfasserin aut Kwok-Fai Lau verfasserin aut Jacky Chi Ki Ngo verfasserin aut Ho Yin Edwin Chan verfasserin aut In Molecular Therapy: Nucleic Acids Elsevier, 2013 16(2019), Seite 172-185 (DE-627)718632702 (DE-600)2662631-7 21622531 nnns volume:16 year:2019 pages:172-185 https://doi.org/10.1016/j.omtn.2019.02.015 kostenfrei https://doaj.org/article/93a3c017448d49dfb54ad5fc338c760b kostenfrei http://www.sciencedirect.com/science/article/pii/S2162253119300459 kostenfrei https://doaj.org/toc/2162-2531 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 16 2019 172-185
spelling	10.1016/j.omtn.2019.02.015 doi (DE-627)DOAJ019339992 (DE-599)DOAJ93a3c017448d49dfb54ad5fc338c760b DE-627 ger DE-627 rakwb eng RM1-950 Qian Zhang verfasserin aut A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier One drug, two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV, TAT-BIND reduces cell death, formation of GGGGCC RNA foci, and levels of poly-GR, poly-GA, and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein, restores rRNA maturation, and inhibits mislocalization of nucleolin and B23, which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD, TAT-BIND suppresses retinal degeneration, rescues climbing ability, and extends the lifespan of flies. In contrast, TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)100-expressing flies, which generate only poly-GR protein toxicity, indicating BIND ameliorates toxicity in C9ALS-FTD models via a r(GGGGCC)exp-dependent inhibitory mechanism. Our findings demonstrated that, apart from being a potential therapeutic for polyQ diseases, BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration, highlighting its potential application in C9ALS-FTD treatment. Keywords: G4C2, amyotrophic lateral sclerosis, frontotemporal dementia, cell-penetrating peptide, peptide inhibitor, C9ORF72 Therapeutics. Pharmacology Ying An verfasserin aut Zhefan Stephen Chen verfasserin aut Alex Chun Koon verfasserin aut Kwok-Fai Lau verfasserin aut Jacky Chi Ki Ngo verfasserin aut Ho Yin Edwin Chan verfasserin aut In Molecular Therapy: Nucleic Acids Elsevier, 2013 16(2019), Seite 172-185 (DE-627)718632702 (DE-600)2662631-7 21622531 nnns volume:16 year:2019 pages:172-185 https://doi.org/10.1016/j.omtn.2019.02.015 kostenfrei https://doaj.org/article/93a3c017448d49dfb54ad5fc338c760b kostenfrei http://www.sciencedirect.com/science/article/pii/S2162253119300459 kostenfrei https://doaj.org/toc/2162-2531 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 16 2019 172-185
allfields_unstemmed	10.1016/j.omtn.2019.02.015 doi (DE-627)DOAJ019339992 (DE-599)DOAJ93a3c017448d49dfb54ad5fc338c760b DE-627 ger DE-627 rakwb eng RM1-950 Qian Zhang verfasserin aut A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier One drug, two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV, TAT-BIND reduces cell death, formation of GGGGCC RNA foci, and levels of poly-GR, poly-GA, and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein, restores rRNA maturation, and inhibits mislocalization of nucleolin and B23, which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD, TAT-BIND suppresses retinal degeneration, rescues climbing ability, and extends the lifespan of flies. In contrast, TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)100-expressing flies, which generate only poly-GR protein toxicity, indicating BIND ameliorates toxicity in C9ALS-FTD models via a r(GGGGCC)exp-dependent inhibitory mechanism. Our findings demonstrated that, apart from being a potential therapeutic for polyQ diseases, BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration, highlighting its potential application in C9ALS-FTD treatment. Keywords: G4C2, amyotrophic lateral sclerosis, frontotemporal dementia, cell-penetrating peptide, peptide inhibitor, C9ORF72 Therapeutics. Pharmacology Ying An verfasserin aut Zhefan Stephen Chen verfasserin aut Alex Chun Koon verfasserin aut Kwok-Fai Lau verfasserin aut Jacky Chi Ki Ngo verfasserin aut Ho Yin Edwin Chan verfasserin aut In Molecular Therapy: Nucleic Acids Elsevier, 2013 16(2019), Seite 172-185 (DE-627)718632702 (DE-600)2662631-7 21622531 nnns volume:16 year:2019 pages:172-185 https://doi.org/10.1016/j.omtn.2019.02.015 kostenfrei https://doaj.org/article/93a3c017448d49dfb54ad5fc338c760b kostenfrei http://www.sciencedirect.com/science/article/pii/S2162253119300459 kostenfrei https://doaj.org/toc/2162-2531 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 16 2019 172-185
allfieldsGer	10.1016/j.omtn.2019.02.015 doi (DE-627)DOAJ019339992 (DE-599)DOAJ93a3c017448d49dfb54ad5fc338c760b DE-627 ger DE-627 rakwb eng RM1-950 Qian Zhang verfasserin aut A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier One drug, two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV, TAT-BIND reduces cell death, formation of GGGGCC RNA foci, and levels of poly-GR, poly-GA, and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein, restores rRNA maturation, and inhibits mislocalization of nucleolin and B23, which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD, TAT-BIND suppresses retinal degeneration, rescues climbing ability, and extends the lifespan of flies. In contrast, TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)100-expressing flies, which generate only poly-GR protein toxicity, indicating BIND ameliorates toxicity in C9ALS-FTD models via a r(GGGGCC)exp-dependent inhibitory mechanism. Our findings demonstrated that, apart from being a potential therapeutic for polyQ diseases, BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration, highlighting its potential application in C9ALS-FTD treatment. Keywords: G4C2, amyotrophic lateral sclerosis, frontotemporal dementia, cell-penetrating peptide, peptide inhibitor, C9ORF72 Therapeutics. Pharmacology Ying An verfasserin aut Zhefan Stephen Chen verfasserin aut Alex Chun Koon verfasserin aut Kwok-Fai Lau verfasserin aut Jacky Chi Ki Ngo verfasserin aut Ho Yin Edwin Chan verfasserin aut In Molecular Therapy: Nucleic Acids Elsevier, 2013 16(2019), Seite 172-185 (DE-627)718632702 (DE-600)2662631-7 21622531 nnns volume:16 year:2019 pages:172-185 https://doi.org/10.1016/j.omtn.2019.02.015 kostenfrei https://doaj.org/article/93a3c017448d49dfb54ad5fc338c760b kostenfrei http://www.sciencedirect.com/science/article/pii/S2162253119300459 kostenfrei https://doaj.org/toc/2162-2531 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 16 2019 172-185
allfieldsSound	10.1016/j.omtn.2019.02.015 doi (DE-627)DOAJ019339992 (DE-599)DOAJ93a3c017448d49dfb54ad5fc338c760b DE-627 ger DE-627 rakwb eng RM1-950 Qian Zhang verfasserin aut A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier One drug, two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV, TAT-BIND reduces cell death, formation of GGGGCC RNA foci, and levels of poly-GR, poly-GA, and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein, restores rRNA maturation, and inhibits mislocalization of nucleolin and B23, which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD, TAT-BIND suppresses retinal degeneration, rescues climbing ability, and extends the lifespan of flies. In contrast, TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)100-expressing flies, which generate only poly-GR protein toxicity, indicating BIND ameliorates toxicity in C9ALS-FTD models via a r(GGGGCC)exp-dependent inhibitory mechanism. Our findings demonstrated that, apart from being a potential therapeutic for polyQ diseases, BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration, highlighting its potential application in C9ALS-FTD treatment. Keywords: G4C2, amyotrophic lateral sclerosis, frontotemporal dementia, cell-penetrating peptide, peptide inhibitor, C9ORF72 Therapeutics. Pharmacology Ying An verfasserin aut Zhefan Stephen Chen verfasserin aut Alex Chun Koon verfasserin aut Kwok-Fai Lau verfasserin aut Jacky Chi Ki Ngo verfasserin aut Ho Yin Edwin Chan verfasserin aut In Molecular Therapy: Nucleic Acids Elsevier, 2013 16(2019), Seite 172-185 (DE-627)718632702 (DE-600)2662631-7 21622531 nnns volume:16 year:2019 pages:172-185 https://doi.org/10.1016/j.omtn.2019.02.015 kostenfrei https://doaj.org/article/93a3c017448d49dfb54ad5fc338c760b kostenfrei http://www.sciencedirect.com/science/article/pii/S2162253119300459 kostenfrei https://doaj.org/toc/2162-2531 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 16 2019 172-185
language	English
source	In Molecular Therapy: Nucleic Acids 16(2019), Seite 172-185 volume:16 year:2019 pages:172-185
sourceStr	In Molecular Therapy: Nucleic Acids 16(2019), Seite 172-185 volume:16 year:2019 pages:172-185
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Therapeutics. Pharmacology
isfreeaccess_bool	true
container_title	Molecular Therapy: Nucleic Acids
authorswithroles_txt_mv	Qian Zhang @@aut@@ Ying An @@aut@@ Zhefan Stephen Chen @@aut@@ Alex Chun Koon @@aut@@ Kwok-Fai Lau @@aut@@ Jacky Chi Ki Ngo @@aut@@ Ho Yin Edwin Chan @@aut@@
publishDateDaySort_date	2019-01-01T00:00:00Z
hierarchy_top_id	718632702
id	DOAJ019339992
language_de	englisch
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callnumber-first	R - Medicine
author	Qian Zhang
spellingShingle	Qian Zhang misc RM1-950 misc Therapeutics. Pharmacology A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD
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topic_title	RM1-950 A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD
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title	A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD
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title_full	A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD
author_sort	Qian Zhang
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author_browse	Qian Zhang Ying An Zhefan Stephen Chen Alex Chun Koon Kwok-Fai Lau Jacky Chi Ki Ngo Ho Yin Edwin Chan
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title_sort	peptidylic inhibitor for neutralizing r(ggggcc)exp-associated neurodegeneration in c9als-ftd
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title_auth	A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD
abstract	One drug, two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV, TAT-BIND reduces cell death, formation of GGGGCC RNA foci, and levels of poly-GR, poly-GA, and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein, restores rRNA maturation, and inhibits mislocalization of nucleolin and B23, which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD, TAT-BIND suppresses retinal degeneration, rescues climbing ability, and extends the lifespan of flies. In contrast, TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)100-expressing flies, which generate only poly-GR protein toxicity, indicating BIND ameliorates toxicity in C9ALS-FTD models via a r(GGGGCC)exp-dependent inhibitory mechanism. Our findings demonstrated that, apart from being a potential therapeutic for polyQ diseases, BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration, highlighting its potential application in C9ALS-FTD treatment. Keywords: G4C2, amyotrophic lateral sclerosis, frontotemporal dementia, cell-penetrating peptide, peptide inhibitor, C9ORF72
abstractGer	One drug, two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV, TAT-BIND reduces cell death, formation of GGGGCC RNA foci, and levels of poly-GR, poly-GA, and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein, restores rRNA maturation, and inhibits mislocalization of nucleolin and B23, which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD, TAT-BIND suppresses retinal degeneration, rescues climbing ability, and extends the lifespan of flies. In contrast, TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)100-expressing flies, which generate only poly-GR protein toxicity, indicating BIND ameliorates toxicity in C9ALS-FTD models via a r(GGGGCC)exp-dependent inhibitory mechanism. Our findings demonstrated that, apart from being a potential therapeutic for polyQ diseases, BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration, highlighting its potential application in C9ALS-FTD treatment. Keywords: G4C2, amyotrophic lateral sclerosis, frontotemporal dementia, cell-penetrating peptide, peptide inhibitor, C9ORF72
abstract_unstemmed	One drug, two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV, TAT-BIND reduces cell death, formation of GGGGCC RNA foci, and levels of poly-GR, poly-GA, and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein, restores rRNA maturation, and inhibits mislocalization of nucleolin and B23, which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD, TAT-BIND suppresses retinal degeneration, rescues climbing ability, and extends the lifespan of flies. In contrast, TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)100-expressing flies, which generate only poly-GR protein toxicity, indicating BIND ameliorates toxicity in C9ALS-FTD models via a r(GGGGCC)exp-dependent inhibitory mechanism. Our findings demonstrated that, apart from being a potential therapeutic for polyQ diseases, BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration, highlighting its potential application in C9ALS-FTD treatment. Keywords: G4C2, amyotrophic lateral sclerosis, frontotemporal dementia, cell-penetrating peptide, peptide inhibitor, C9ORF72
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title_short	A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD
url	https://doi.org/10.1016/j.omtn.2019.02.015 https://doaj.org/article/93a3c017448d49dfb54ad5fc338c760b http://www.sciencedirect.com/science/article/pii/S2162253119300459 https://doaj.org/toc/2162-2531
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We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV, TAT-BIND reduces cell death, formation of GGGGCC RNA foci, and levels of poly-GR, poly-GA, and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein, restores rRNA maturation, and inhibits mislocalization of nucleolin and B23, which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD, TAT-BIND suppresses retinal degeneration, rescues climbing ability, and extends the lifespan of flies. In contrast, TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)100-expressing flies, which generate only poly-GR protein toxicity, indicating BIND ameliorates toxicity in C9ALS-FTD models via a r(GGGGCC)exp-dependent inhibitory mechanism. Our findings demonstrated that, apart from being a potential therapeutic for polyQ diseases, BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration, highlighting its potential application in C9ALS-FTD treatment. Keywords: G4C2, amyotrophic lateral sclerosis, frontotemporal dementia, cell-penetrating peptide, peptide inhibitor, C9ORF72</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Therapeutics. 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A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD

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