Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis
Abstract Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characte...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Scekic-Zahirovic, Jelena [verfasserIn] Oussini, Hajer El [verfasserIn] Mersmann, Sina [verfasserIn] Drenner, Kevin [verfasserIn] Wagner, Marina [verfasserIn] Sun, Ying [verfasserIn] Allmeroth, Kira [verfasserIn] Dieterlé, Stéphane [verfasserIn] Sinniger, Jérôme [verfasserIn] Dirrig-Grosch, Sylvie [verfasserIn] René, Frédérique [verfasserIn] Dormann, Dorothee [verfasserIn] Haass, Christian [verfasserIn] Ludolph, Albert C. [verfasserIn] Lagier-Tourenne, Clotilde [verfasserIn] Storkebaum, Erik [verfasserIn] Dupuis, Luc [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2017 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Acta neuropathologica - Berlin : Springer, 1961, 133(2017), 6 vom: 28. Feb., Seite 887-906 |
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| Übergeordnetes Werk: |
volume:133 ; year:2017 ; number:6 ; day:28 ; month:02 ; pages:887-906 |
| Links: |
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| DOI / URN: |
10.1007/s00401-017-1687-9 |
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| Katalog-ID: |
SPR004991311 |
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| 245 | 1 | 0 | |a Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis |
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| 520 | |a Abstract Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease. | ||
| 650 | 4 | |a Amyotrophic lateral sclerosis |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Fronto-temporal dementia |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Mouse models |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Non-cell autonomous mechanisms |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a RNA-binding proteins |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Oussini, Hajer El |e verfasserin |4 aut | |
| 700 | 1 | |a Mersmann, Sina |e verfasserin |4 aut | |
| 700 | 1 | |a Drenner, Kevin |e verfasserin |4 aut | |
| 700 | 1 | |a Wagner, Marina |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Allmeroth, Kira |e verfasserin |4 aut | |
| 700 | 1 | |a Dieterlé, Stéphane |e verfasserin |4 aut | |
| 700 | 1 | |a Sinniger, Jérôme |e verfasserin |4 aut | |
| 700 | 1 | |a Dirrig-Grosch, Sylvie |e verfasserin |4 aut | |
| 700 | 1 | |a René, Frédérique |e verfasserin |4 aut | |
| 700 | 1 | |a Dormann, Dorothee |e verfasserin |4 aut | |
| 700 | 1 | |a Haass, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Ludolph, Albert C. |e verfasserin |4 aut | |
| 700 | 1 | |a Lagier-Tourenne, Clotilde |e verfasserin |4 aut | |
| 700 | 1 | |a Storkebaum, Erik |e verfasserin |4 aut | |
| 700 | 1 | |a Dupuis, Luc |e verfasserin |4 aut | |
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10.1007/s00401-017-1687-9 doi (DE-627)SPR004991311 (SPR)s00401-017-1687-9-e DE-627 ger DE-627 rakwb eng 610 ASE 44.90 bkl Scekic-Zahirovic, Jelena verfasserin aut Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease. Amyotrophic lateral sclerosis (dpeaa)DE-He213 Fronto-temporal dementia (dpeaa)DE-He213 Mouse models (dpeaa)DE-He213 Non-cell autonomous mechanisms (dpeaa)DE-He213 RNA-binding proteins (dpeaa)DE-He213 Oussini, Hajer El verfasserin aut Mersmann, Sina verfasserin aut Drenner, Kevin verfasserin aut Wagner, Marina verfasserin aut Sun, Ying verfasserin aut Allmeroth, Kira verfasserin aut Dieterlé, Stéphane verfasserin aut Sinniger, Jérôme verfasserin aut Dirrig-Grosch, Sylvie verfasserin aut René, Frédérique verfasserin aut Dormann, Dorothee verfasserin aut Haass, Christian verfasserin aut Ludolph, Albert C. verfasserin aut Lagier-Tourenne, Clotilde verfasserin aut Storkebaum, Erik verfasserin aut Dupuis, Luc verfasserin aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 133(2017), 6 vom: 28. Feb., Seite 887-906 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:133 year:2017 number:6 day:28 month:02 pages:887-906 https://dx.doi.org/10.1007/s00401-017-1687-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 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_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 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_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 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_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 133 2017 6 28 02 887-906 |
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10.1007/s00401-017-1687-9 doi (DE-627)SPR004991311 (SPR)s00401-017-1687-9-e DE-627 ger DE-627 rakwb eng 610 ASE 44.90 bkl Scekic-Zahirovic, Jelena verfasserin aut Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease. Amyotrophic lateral sclerosis (dpeaa)DE-He213 Fronto-temporal dementia (dpeaa)DE-He213 Mouse models (dpeaa)DE-He213 Non-cell autonomous mechanisms (dpeaa)DE-He213 RNA-binding proteins (dpeaa)DE-He213 Oussini, Hajer El verfasserin aut Mersmann, Sina verfasserin aut Drenner, Kevin verfasserin aut Wagner, Marina verfasserin aut Sun, Ying verfasserin aut Allmeroth, Kira verfasserin aut Dieterlé, Stéphane verfasserin aut Sinniger, Jérôme verfasserin aut Dirrig-Grosch, Sylvie verfasserin aut René, Frédérique verfasserin aut Dormann, Dorothee verfasserin aut Haass, Christian verfasserin aut Ludolph, Albert C. verfasserin aut Lagier-Tourenne, Clotilde verfasserin aut Storkebaum, Erik verfasserin aut Dupuis, Luc verfasserin aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 133(2017), 6 vom: 28. Feb., Seite 887-906 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:133 year:2017 number:6 day:28 month:02 pages:887-906 https://dx.doi.org/10.1007/s00401-017-1687-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 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_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 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_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 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_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 133 2017 6 28 02 887-906 |
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10.1007/s00401-017-1687-9 doi (DE-627)SPR004991311 (SPR)s00401-017-1687-9-e DE-627 ger DE-627 rakwb eng 610 ASE 44.90 bkl Scekic-Zahirovic, Jelena verfasserin aut Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease. Amyotrophic lateral sclerosis (dpeaa)DE-He213 Fronto-temporal dementia (dpeaa)DE-He213 Mouse models (dpeaa)DE-He213 Non-cell autonomous mechanisms (dpeaa)DE-He213 RNA-binding proteins (dpeaa)DE-He213 Oussini, Hajer El verfasserin aut Mersmann, Sina verfasserin aut Drenner, Kevin verfasserin aut Wagner, Marina verfasserin aut Sun, Ying verfasserin aut Allmeroth, Kira verfasserin aut Dieterlé, Stéphane verfasserin aut Sinniger, Jérôme verfasserin aut Dirrig-Grosch, Sylvie verfasserin aut René, Frédérique verfasserin aut Dormann, Dorothee verfasserin aut Haass, Christian verfasserin aut Ludolph, Albert C. verfasserin aut Lagier-Tourenne, Clotilde verfasserin aut Storkebaum, Erik verfasserin aut Dupuis, Luc verfasserin aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 133(2017), 6 vom: 28. Feb., Seite 887-906 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:133 year:2017 number:6 day:28 month:02 pages:887-906 https://dx.doi.org/10.1007/s00401-017-1687-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 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_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 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_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 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_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 133 2017 6 28 02 887-906 |
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10.1007/s00401-017-1687-9 doi (DE-627)SPR004991311 (SPR)s00401-017-1687-9-e DE-627 ger DE-627 rakwb eng 610 ASE 44.90 bkl Scekic-Zahirovic, Jelena verfasserin aut Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease. Amyotrophic lateral sclerosis (dpeaa)DE-He213 Fronto-temporal dementia (dpeaa)DE-He213 Mouse models (dpeaa)DE-He213 Non-cell autonomous mechanisms (dpeaa)DE-He213 RNA-binding proteins (dpeaa)DE-He213 Oussini, Hajer El verfasserin aut Mersmann, Sina verfasserin aut Drenner, Kevin verfasserin aut Wagner, Marina verfasserin aut Sun, Ying verfasserin aut Allmeroth, Kira verfasserin aut Dieterlé, Stéphane verfasserin aut Sinniger, Jérôme verfasserin aut Dirrig-Grosch, Sylvie verfasserin aut René, Frédérique verfasserin aut Dormann, Dorothee verfasserin aut Haass, Christian verfasserin aut Ludolph, Albert C. verfasserin aut Lagier-Tourenne, Clotilde verfasserin aut Storkebaum, Erik verfasserin aut Dupuis, Luc verfasserin aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 133(2017), 6 vom: 28. Feb., Seite 887-906 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:133 year:2017 number:6 day:28 month:02 pages:887-906 https://dx.doi.org/10.1007/s00401-017-1687-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 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_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 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_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 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_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 133 2017 6 28 02 887-906 |
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10.1007/s00401-017-1687-9 doi (DE-627)SPR004991311 (SPR)s00401-017-1687-9-e DE-627 ger DE-627 rakwb eng 610 ASE 44.90 bkl Scekic-Zahirovic, Jelena verfasserin aut Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease. Amyotrophic lateral sclerosis (dpeaa)DE-He213 Fronto-temporal dementia (dpeaa)DE-He213 Mouse models (dpeaa)DE-He213 Non-cell autonomous mechanisms (dpeaa)DE-He213 RNA-binding proteins (dpeaa)DE-He213 Oussini, Hajer El verfasserin aut Mersmann, Sina verfasserin aut Drenner, Kevin verfasserin aut Wagner, Marina verfasserin aut Sun, Ying verfasserin aut Allmeroth, Kira verfasserin aut Dieterlé, Stéphane verfasserin aut Sinniger, Jérôme verfasserin aut Dirrig-Grosch, Sylvie verfasserin aut René, Frédérique verfasserin aut Dormann, Dorothee verfasserin aut Haass, Christian verfasserin aut Ludolph, Albert C. verfasserin aut Lagier-Tourenne, Clotilde verfasserin aut Storkebaum, Erik verfasserin aut Dupuis, Luc verfasserin aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 133(2017), 6 vom: 28. Feb., Seite 887-906 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:133 year:2017 number:6 day:28 month:02 pages:887-906 https://dx.doi.org/10.1007/s00401-017-1687-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 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_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 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_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 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_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 133 2017 6 28 02 887-906 |
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Enthalten in Acta neuropathologica 133(2017), 6 vom: 28. Feb., Seite 887-906 volume:133 year:2017 number:6 day:28 month:02 pages:887-906 |
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Enthalten in Acta neuropathologica 133(2017), 6 vom: 28. Feb., Seite 887-906 volume:133 year:2017 number:6 day:28 month:02 pages:887-906 |
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Amyotrophic lateral sclerosis Fronto-temporal dementia Mouse models Non-cell autonomous mechanisms RNA-binding proteins |
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Scekic-Zahirovic, Jelena @@aut@@ Oussini, Hajer El @@aut@@ Mersmann, Sina @@aut@@ Drenner, Kevin @@aut@@ Wagner, Marina @@aut@@ Sun, Ying @@aut@@ Allmeroth, Kira @@aut@@ Dieterlé, Stéphane @@aut@@ Sinniger, Jérôme @@aut@@ Dirrig-Grosch, Sylvie @@aut@@ René, Frédérique @@aut@@ Dormann, Dorothee @@aut@@ Haass, Christian @@aut@@ Ludolph, Albert C. @@aut@@ Lagier-Tourenne, Clotilde @@aut@@ Storkebaum, Erik @@aut@@ Dupuis, Luc @@aut@@ |
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It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. 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|
| author |
Scekic-Zahirovic, Jelena |
| spellingShingle |
Scekic-Zahirovic, Jelena ddc 610 bkl 44.90 misc Amyotrophic lateral sclerosis misc Fronto-temporal dementia misc Mouse models misc Non-cell autonomous mechanisms misc RNA-binding proteins Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis |
| authorStr |
Scekic-Zahirovic, Jelena |
| ppnlink_with_tag_str_mv |
@@773@@(DE-627)253389666 |
| format |
electronic Article |
| dewey-ones |
610 - Medicine & health |
| delete_txt_mv |
keep |
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aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut |
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springer |
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true |
| illustrated |
Not Illustrated |
| issn |
1432-0533 |
| topic_title |
610 ASE 44.90 bkl Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (dpeaa)DE-He213 Fronto-temporal dementia (dpeaa)DE-He213 Mouse models (dpeaa)DE-He213 Non-cell autonomous mechanisms (dpeaa)DE-He213 RNA-binding proteins (dpeaa)DE-He213 |
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Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis |
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Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis |
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Scekic-Zahirovic, Jelena |
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Scekic-Zahirovic, Jelena Oussini, Hajer El Mersmann, Sina Drenner, Kevin Wagner, Marina Sun, Ying Allmeroth, Kira Dieterlé, Stéphane Sinniger, Jérôme Dirrig-Grosch, Sylvie René, Frédérique Dormann, Dorothee Haass, Christian Ludolph, Albert C. Lagier-Tourenne, Clotilde Storkebaum, Erik Dupuis, Luc |
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motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of fus-associated amyotrophic lateral sclerosis |
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Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis |
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Abstract Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease. |
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Abstract Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease. |
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Abstract Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease. |
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| score |
7.402231 |