The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS
Abstract Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumula...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Kawabe, Yuya [verfasserIn] Mori, Kohji [verfasserIn] Yamashita, Tomoko [verfasserIn] Gotoh, Shiho [verfasserIn] Ikeda, Manabu [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2020 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2020 |
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| Übergeordnetes Werk: |
Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 39(2020), 19 vom: 24. Aug. |
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| Übergeordnetes Werk: |
volume:39 ; year:2020 ; number:19 ; day:24 ; month:08 |
| Links: |
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| DOI / URN: |
10.15252/embj.2019102700 |
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| Katalog-ID: |
SPR058065687 |
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| 100 | 1 | |a Kawabe, Yuya |e verfasserin |0 (orcid)0000-0002-5438-4797 |4 aut | |
| 245 | 1 | 0 | |a The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS |
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| 520 | |a Abstract Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72‐derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient‐derived cells. Cells expressing toxic poly‐GR or poly‐PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine‐rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine‐rich DPR‐mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72‐FTLD/ALS pathologies in a vicious cycle. | ||
| 520 | |a Synopsis Bidirectional transcription and translation of the FTLD/ALS‐associated repeat expansion in the C9orf72 gene causes accumulation of repeat RNA foci and toxic dipeptide‐repeat proteins. Here, the RNA exosome is found to degrade repeat RNAs, until overwhelmed by inhibitory effects of the toxic repeat proteins. Knockdown of the exosome catalytic subunit EXOSC10 causes accumulation and foci formation of repeat RNA.EXOSC10 can degrade sense and antisense strand‐derived expanded hexanucleotide repeat RNA.EXOSC10 knockdown boosts dipeptide repeat protein expression through RAN translation.Arginine‐rich dipeptide repeat proteins impair the activity of EXOSC10 and thereby accelerate repeat RNA and dipeptide repeat protein accumulation. | ||
| 520 | |a Graphical Abstract The exosome has a key role in curbing accumulation of toxic dipeptide‐repeat proteins, which in turn can impair exosome activity and thereby exacerbate neurodegenerative pathologies. | ||
| 650 | 4 | |a dipeptide repeat proteins |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a DIS3 |7 (dpeaa)DE-He213 | |
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| 650 | 4 | |a RNA metabolism in neurodegeneration |7 (dpeaa)DE-He213 | |
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| 700 | 1 | |a Yamashita, Tomoko |e verfasserin |4 aut | |
| 700 | 1 | |a Gotoh, Shiho |e verfasserin |0 (orcid)0000-0002-7068-4538 |4 aut | |
| 700 | 1 | |a Ikeda, Manabu |e verfasserin |4 aut | |
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10.15252/embj.2019102700 doi (DE-627)SPR058065687 (SPR)embj.2019102700-e DE-627 ger DE-627 rakwb eng Kawabe, Yuya verfasserin (orcid)0000-0002-5438-4797 aut The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72‐derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient‐derived cells. Cells expressing toxic poly‐GR or poly‐PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine‐rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine‐rich DPR‐mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72‐FTLD/ALS pathologies in a vicious cycle. Synopsis Bidirectional transcription and translation of the FTLD/ALS‐associated repeat expansion in the C9orf72 gene causes accumulation of repeat RNA foci and toxic dipeptide‐repeat proteins. Here, the RNA exosome is found to degrade repeat RNAs, until overwhelmed by inhibitory effects of the toxic repeat proteins. Knockdown of the exosome catalytic subunit EXOSC10 causes accumulation and foci formation of repeat RNA.EXOSC10 can degrade sense and antisense strand‐derived expanded hexanucleotide repeat RNA.EXOSC10 knockdown boosts dipeptide repeat protein expression through RAN translation.Arginine‐rich dipeptide repeat proteins impair the activity of EXOSC10 and thereby accelerate repeat RNA and dipeptide repeat protein accumulation. Graphical Abstract The exosome has a key role in curbing accumulation of toxic dipeptide‐repeat proteins, which in turn can impair exosome activity and thereby exacerbate neurodegenerative pathologies. dipeptide repeat proteins (dpeaa)DE-He213 DIS3 (dpeaa)DE-He213 EXOSC10 (dpeaa)DE-He213 RAN translation (dpeaa)DE-He213 RNA metabolism in neurodegeneration (dpeaa)DE-He213 Mori, Kohji verfasserin (orcid)0000-0003-2629-0723 aut Yamashita, Tomoko verfasserin aut Gotoh, Shiho verfasserin (orcid)0000-0002-7068-4538 aut Ikeda, Manabu verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 19 vom: 24. Aug. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:19 day:24 month:08 https://dx.doi.org/10.15252/embj.2019102700 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 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_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 19 24 08 |
| spelling |
10.15252/embj.2019102700 doi (DE-627)SPR058065687 (SPR)embj.2019102700-e DE-627 ger DE-627 rakwb eng Kawabe, Yuya verfasserin (orcid)0000-0002-5438-4797 aut The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72‐derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient‐derived cells. Cells expressing toxic poly‐GR or poly‐PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine‐rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine‐rich DPR‐mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72‐FTLD/ALS pathologies in a vicious cycle. Synopsis Bidirectional transcription and translation of the FTLD/ALS‐associated repeat expansion in the C9orf72 gene causes accumulation of repeat RNA foci and toxic dipeptide‐repeat proteins. Here, the RNA exosome is found to degrade repeat RNAs, until overwhelmed by inhibitory effects of the toxic repeat proteins. Knockdown of the exosome catalytic subunit EXOSC10 causes accumulation and foci formation of repeat RNA.EXOSC10 can degrade sense and antisense strand‐derived expanded hexanucleotide repeat RNA.EXOSC10 knockdown boosts dipeptide repeat protein expression through RAN translation.Arginine‐rich dipeptide repeat proteins impair the activity of EXOSC10 and thereby accelerate repeat RNA and dipeptide repeat protein accumulation. Graphical Abstract The exosome has a key role in curbing accumulation of toxic dipeptide‐repeat proteins, which in turn can impair exosome activity and thereby exacerbate neurodegenerative pathologies. dipeptide repeat proteins (dpeaa)DE-He213 DIS3 (dpeaa)DE-He213 EXOSC10 (dpeaa)DE-He213 RAN translation (dpeaa)DE-He213 RNA metabolism in neurodegeneration (dpeaa)DE-He213 Mori, Kohji verfasserin (orcid)0000-0003-2629-0723 aut Yamashita, Tomoko verfasserin aut Gotoh, Shiho verfasserin (orcid)0000-0002-7068-4538 aut Ikeda, Manabu verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 19 vom: 24. Aug. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:19 day:24 month:08 https://dx.doi.org/10.15252/embj.2019102700 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 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_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 19 24 08 |
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10.15252/embj.2019102700 doi (DE-627)SPR058065687 (SPR)embj.2019102700-e DE-627 ger DE-627 rakwb eng Kawabe, Yuya verfasserin (orcid)0000-0002-5438-4797 aut The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72‐derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient‐derived cells. Cells expressing toxic poly‐GR or poly‐PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine‐rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine‐rich DPR‐mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72‐FTLD/ALS pathologies in a vicious cycle. Synopsis Bidirectional transcription and translation of the FTLD/ALS‐associated repeat expansion in the C9orf72 gene causes accumulation of repeat RNA foci and toxic dipeptide‐repeat proteins. Here, the RNA exosome is found to degrade repeat RNAs, until overwhelmed by inhibitory effects of the toxic repeat proteins. Knockdown of the exosome catalytic subunit EXOSC10 causes accumulation and foci formation of repeat RNA.EXOSC10 can degrade sense and antisense strand‐derived expanded hexanucleotide repeat RNA.EXOSC10 knockdown boosts dipeptide repeat protein expression through RAN translation.Arginine‐rich dipeptide repeat proteins impair the activity of EXOSC10 and thereby accelerate repeat RNA and dipeptide repeat protein accumulation. Graphical Abstract The exosome has a key role in curbing accumulation of toxic dipeptide‐repeat proteins, which in turn can impair exosome activity and thereby exacerbate neurodegenerative pathologies. dipeptide repeat proteins (dpeaa)DE-He213 DIS3 (dpeaa)DE-He213 EXOSC10 (dpeaa)DE-He213 RAN translation (dpeaa)DE-He213 RNA metabolism in neurodegeneration (dpeaa)DE-He213 Mori, Kohji verfasserin (orcid)0000-0003-2629-0723 aut Yamashita, Tomoko verfasserin aut Gotoh, Shiho verfasserin (orcid)0000-0002-7068-4538 aut Ikeda, Manabu verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 19 vom: 24. Aug. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:19 day:24 month:08 https://dx.doi.org/10.15252/embj.2019102700 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 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_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 19 24 08 |
| allfieldsGer |
10.15252/embj.2019102700 doi (DE-627)SPR058065687 (SPR)embj.2019102700-e DE-627 ger DE-627 rakwb eng Kawabe, Yuya verfasserin (orcid)0000-0002-5438-4797 aut The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72‐derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient‐derived cells. Cells expressing toxic poly‐GR or poly‐PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine‐rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine‐rich DPR‐mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72‐FTLD/ALS pathologies in a vicious cycle. Synopsis Bidirectional transcription and translation of the FTLD/ALS‐associated repeat expansion in the C9orf72 gene causes accumulation of repeat RNA foci and toxic dipeptide‐repeat proteins. Here, the RNA exosome is found to degrade repeat RNAs, until overwhelmed by inhibitory effects of the toxic repeat proteins. Knockdown of the exosome catalytic subunit EXOSC10 causes accumulation and foci formation of repeat RNA.EXOSC10 can degrade sense and antisense strand‐derived expanded hexanucleotide repeat RNA.EXOSC10 knockdown boosts dipeptide repeat protein expression through RAN translation.Arginine‐rich dipeptide repeat proteins impair the activity of EXOSC10 and thereby accelerate repeat RNA and dipeptide repeat protein accumulation. Graphical Abstract The exosome has a key role in curbing accumulation of toxic dipeptide‐repeat proteins, which in turn can impair exosome activity and thereby exacerbate neurodegenerative pathologies. dipeptide repeat proteins (dpeaa)DE-He213 DIS3 (dpeaa)DE-He213 EXOSC10 (dpeaa)DE-He213 RAN translation (dpeaa)DE-He213 RNA metabolism in neurodegeneration (dpeaa)DE-He213 Mori, Kohji verfasserin (orcid)0000-0003-2629-0723 aut Yamashita, Tomoko verfasserin aut Gotoh, Shiho verfasserin (orcid)0000-0002-7068-4538 aut Ikeda, Manabu verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 19 vom: 24. Aug. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:19 day:24 month:08 https://dx.doi.org/10.15252/embj.2019102700 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 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_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 19 24 08 |
| allfieldsSound |
10.15252/embj.2019102700 doi (DE-627)SPR058065687 (SPR)embj.2019102700-e DE-627 ger DE-627 rakwb eng Kawabe, Yuya verfasserin (orcid)0000-0002-5438-4797 aut The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72‐derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient‐derived cells. Cells expressing toxic poly‐GR or poly‐PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine‐rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine‐rich DPR‐mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72‐FTLD/ALS pathologies in a vicious cycle. Synopsis Bidirectional transcription and translation of the FTLD/ALS‐associated repeat expansion in the C9orf72 gene causes accumulation of repeat RNA foci and toxic dipeptide‐repeat proteins. Here, the RNA exosome is found to degrade repeat RNAs, until overwhelmed by inhibitory effects of the toxic repeat proteins. Knockdown of the exosome catalytic subunit EXOSC10 causes accumulation and foci formation of repeat RNA.EXOSC10 can degrade sense and antisense strand‐derived expanded hexanucleotide repeat RNA.EXOSC10 knockdown boosts dipeptide repeat protein expression through RAN translation.Arginine‐rich dipeptide repeat proteins impair the activity of EXOSC10 and thereby accelerate repeat RNA and dipeptide repeat protein accumulation. Graphical Abstract The exosome has a key role in curbing accumulation of toxic dipeptide‐repeat proteins, which in turn can impair exosome activity and thereby exacerbate neurodegenerative pathologies. dipeptide repeat proteins (dpeaa)DE-He213 DIS3 (dpeaa)DE-He213 EXOSC10 (dpeaa)DE-He213 RAN translation (dpeaa)DE-He213 RNA metabolism in neurodegeneration (dpeaa)DE-He213 Mori, Kohji verfasserin (orcid)0000-0003-2629-0723 aut Yamashita, Tomoko verfasserin aut Gotoh, Shiho verfasserin (orcid)0000-0002-7068-4538 aut Ikeda, Manabu verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 19 vom: 24. Aug. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:19 day:24 month:08 https://dx.doi.org/10.15252/embj.2019102700 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 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_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 19 24 08 |
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Enthalten in The EMBO Journal 39(2020), 19 vom: 24. Aug. volume:39 year:2020 number:19 day:24 month:08 |
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Enthalten in The EMBO Journal 39(2020), 19 vom: 24. Aug. volume:39 year:2020 number:19 day:24 month:08 |
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dipeptide repeat proteins DIS3 EXOSC10 RAN translation RNA metabolism in neurodegeneration |
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Kawabe, Yuya @@aut@@ Mori, Kohji @@aut@@ Yamashita, Tomoko @@aut@@ Gotoh, Shiho @@aut@@ Ikeda, Manabu @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058065687</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241025065100.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241025s2020 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/embj.2019102700</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058065687</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)embj.2019102700-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Kawabe, Yuya</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-5438-4797</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2020</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2020</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72‐derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient‐derived cells. Cells expressing toxic poly‐GR or poly‐PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine‐rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine‐rich DPR‐mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72‐FTLD/ALS pathologies in a vicious cycle.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Bidirectional transcription and translation of the FTLD/ALS‐associated repeat expansion in the C9orf72 gene causes accumulation of repeat RNA foci and toxic dipeptide‐repeat proteins. Here, the RNA exosome is found to degrade repeat RNAs, until overwhelmed by inhibitory effects of the toxic repeat proteins. Knockdown of the exosome catalytic subunit EXOSC10 causes accumulation and foci formation of repeat RNA.EXOSC10 can degrade sense and antisense strand‐derived expanded hexanucleotide repeat RNA.EXOSC10 knockdown boosts dipeptide repeat protein expression through RAN translation.Arginine‐rich dipeptide repeat proteins impair the activity of EXOSC10 and thereby accelerate repeat RNA and dipeptide repeat protein accumulation.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract The exosome has a key role in curbing accumulation of toxic dipeptide‐repeat proteins, which in turn can impair exosome activity and thereby exacerbate neurodegenerative pathologies.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">dipeptide repeat proteins</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">DIS3</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">EXOSC10</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">RAN translation</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">RNA metabolism in neurodegeneration</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Mori, Kohji</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0003-2629-0723</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Yamashita, Tomoko</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Gotoh, Shiho</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-7068-4538</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Ikeda, Manabu</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">The EMBO Journal</subfield><subfield code="d">Nature Publishing Group UK, 2023</subfield><subfield code="g">39(2020), 19 vom: 24. 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|
| author |
Kawabe, Yuya |
| spellingShingle |
Kawabe, Yuya misc dipeptide repeat proteins misc DIS3 misc EXOSC10 misc RAN translation misc RNA metabolism in neurodegeneration The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS |
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Kawabe, Yuya |
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1460-2075 |
| topic_title |
The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS dipeptide repeat proteins (dpeaa)DE-He213 DIS3 (dpeaa)DE-He213 EXOSC10 (dpeaa)DE-He213 RAN translation (dpeaa)DE-He213 RNA metabolism in neurodegeneration (dpeaa)DE-He213 |
| topic |
misc dipeptide repeat proteins misc DIS3 misc EXOSC10 misc RAN translation misc RNA metabolism in neurodegeneration |
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misc dipeptide repeat proteins misc DIS3 misc EXOSC10 misc RAN translation misc RNA metabolism in neurodegeneration |
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misc dipeptide repeat proteins misc DIS3 misc EXOSC10 misc RAN translation misc RNA metabolism in neurodegeneration |
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The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS |
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| title_full |
The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS |
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Kawabe, Yuya |
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The EMBO Journal |
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The EMBO Journal |
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Kawabe, Yuya Mori, Kohji Yamashita, Tomoko Gotoh, Shiho Ikeda, Manabu |
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39 |
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Elektronische Aufsätze |
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Kawabe, Yuya |
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10.15252/embj.2019102700 |
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(ORCID)0000-0002-5438-4797 (ORCID)0000-0003-2629-0723 (ORCID)0000-0002-7068-4538 |
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the rna exosome complex degrades expanded hexanucleotide repeat rna in c9orf72 ftld/als |
| title_auth |
The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS |
| abstract |
Abstract Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72‐derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient‐derived cells. Cells expressing toxic poly‐GR or poly‐PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine‐rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine‐rich DPR‐mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72‐FTLD/ALS pathologies in a vicious cycle. Synopsis Bidirectional transcription and translation of the FTLD/ALS‐associated repeat expansion in the C9orf72 gene causes accumulation of repeat RNA foci and toxic dipeptide‐repeat proteins. Here, the RNA exosome is found to degrade repeat RNAs, until overwhelmed by inhibitory effects of the toxic repeat proteins. Knockdown of the exosome catalytic subunit EXOSC10 causes accumulation and foci formation of repeat RNA.EXOSC10 can degrade sense and antisense strand‐derived expanded hexanucleotide repeat RNA.EXOSC10 knockdown boosts dipeptide repeat protein expression through RAN translation.Arginine‐rich dipeptide repeat proteins impair the activity of EXOSC10 and thereby accelerate repeat RNA and dipeptide repeat protein accumulation. Graphical Abstract The exosome has a key role in curbing accumulation of toxic dipeptide‐repeat proteins, which in turn can impair exosome activity and thereby exacerbate neurodegenerative pathologies. © The Author(s) 2020 |
| abstractGer |
Abstract Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72‐derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient‐derived cells. Cells expressing toxic poly‐GR or poly‐PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine‐rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine‐rich DPR‐mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72‐FTLD/ALS pathologies in a vicious cycle. Synopsis Bidirectional transcription and translation of the FTLD/ALS‐associated repeat expansion in the C9orf72 gene causes accumulation of repeat RNA foci and toxic dipeptide‐repeat proteins. Here, the RNA exosome is found to degrade repeat RNAs, until overwhelmed by inhibitory effects of the toxic repeat proteins. Knockdown of the exosome catalytic subunit EXOSC10 causes accumulation and foci formation of repeat RNA.EXOSC10 can degrade sense and antisense strand‐derived expanded hexanucleotide repeat RNA.EXOSC10 knockdown boosts dipeptide repeat protein expression through RAN translation.Arginine‐rich dipeptide repeat proteins impair the activity of EXOSC10 and thereby accelerate repeat RNA and dipeptide repeat protein accumulation. Graphical Abstract The exosome has a key role in curbing accumulation of toxic dipeptide‐repeat proteins, which in turn can impair exosome activity and thereby exacerbate neurodegenerative pathologies. © The Author(s) 2020 |
| abstract_unstemmed |
Abstract Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72‐derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient‐derived cells. Cells expressing toxic poly‐GR or poly‐PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine‐rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine‐rich DPR‐mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72‐FTLD/ALS pathologies in a vicious cycle. Synopsis Bidirectional transcription and translation of the FTLD/ALS‐associated repeat expansion in the C9orf72 gene causes accumulation of repeat RNA foci and toxic dipeptide‐repeat proteins. Here, the RNA exosome is found to degrade repeat RNAs, until overwhelmed by inhibitory effects of the toxic repeat proteins. Knockdown of the exosome catalytic subunit EXOSC10 causes accumulation and foci formation of repeat RNA.EXOSC10 can degrade sense and antisense strand‐derived expanded hexanucleotide repeat RNA.EXOSC10 knockdown boosts dipeptide repeat protein expression through RAN translation.Arginine‐rich dipeptide repeat proteins impair the activity of EXOSC10 and thereby accelerate repeat RNA and dipeptide repeat protein accumulation. Graphical Abstract The exosome has a key role in curbing accumulation of toxic dipeptide‐repeat proteins, which in turn can impair exosome activity and thereby exacerbate neurodegenerative pathologies. © The Author(s) 2020 |
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| container_issue |
19 |
| title_short |
The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS |
| url |
https://dx.doi.org/10.15252/embj.2019102700 |
| remote_bool |
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| author2 |
Mori, Kohji Yamashita, Tomoko Gotoh, Shiho Ikeda, Manabu |
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Mori, Kohji Yamashita, Tomoko Gotoh, Shiho Ikeda, Manabu |
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| doi_str |
10.15252/embj.2019102700 |
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2024-10-25T04:56:42.242Z |
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| score |
7.401332 |