TDP-43 is a ubiquitylation substrate of the SCF
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons in the brain and spinal cord. ALS and frontotemporal dementia (FTD) are overlapping diseases with shared pathological features. Affected neurons of people w...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Rayner, Stephanie L. [verfasserIn] Yang, Shu [verfasserIn] Farrawell, Natalie E. [verfasserIn] Jagaraj, Cyril J. [verfasserIn] Cheng, Flora [verfasserIn] Davidson, Jennilee M. [verfasserIn] Luu, Luan [verfasserIn] Redondo, Alberto G. [verfasserIn] Rábano, Alberto [verfasserIn] Borrego-Hernández, Daniel [verfasserIn] Atkin, Julie D. [verfasserIn] Morsch, Marco [verfasserIn] Blair, Ian P. [verfasserIn] Yerbury, Justin J. [verfasserIn] Chung, Roger [verfasserIn] Lee, Albert [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Neurobiology of disease - [Amsterdam] : Elsevier, 1994, 167 |
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| Übergeordnetes Werk: |
volume:167 |
| DOI / URN: |
10.1016/j.nbd.2022.105673 |
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| Katalog-ID: |
ELV007613628 |
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| 520 | |a Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons in the brain and spinal cord. ALS and frontotemporal dementia (FTD) are overlapping diseases with shared pathological features. Affected neurons of people with ALS and FTD typically contain ubiquitin-immunoreactive inclusions, of which TDP-43 (Tar DNA-binding protein of 43 kDa) is a major component. However, what triggers the formation of these abnormal TDP-43 inclusions is unclear. Previously, we identified CCNF mutations in cohorts of familial and sporadic cases of ALS and FTD. CCNF encodes cyclin F, the substrate-binding component of a multiprotein E3 ubiquitin ligase complex that ubiquitylates and subsequently directs a set of protein substrates for proteasomal degradation. Here, we explored the relationship between cyclin F and TDP-43.Methods: We used a series of complementary biochemical approaches including immunoprecipitations, in vitro ubiquitylation assays, immunofluorescence imaging and immunocytochemistry. Unpaired student t-tests were used to determine statistical significance of the results.Results: In this study, we demonstrate that that the SCFcyclin F complex directly mediates the poly-ubiquitylation of TDP-43. Importantly, we demonstrate that cyclin F bearing the pathogenic ALS/FTD mutation, S621G, leads to aberrant ubiquitylation of TDP-43 as well as the accumulation of K48-ubiquitylated TDP-43 in neuron-like cells. Furthermore, we demonstrate that a patient carrying the ALS/FTD cyclin FS195R mutation displayed skein-like cytoplasmic TDP-43 aggregates, implying abnormal TDP-43 degradation in a CCNF mutation bearing patient.Conclusion: In summary, this study reports a direct ubiquitylation mechanism for TDP-43, revealing important insights into the regulation of cyclin F-mediated TDP-43 turnover and clues towards understanding the molecular origins of the ubiquitylated TDP-43 inclusions that are the hallmark pathological feature in ALS and FTD. | ||
| 650 | 4 | |a Amyotrophic lateral sclerosis | |
| 650 | 4 | |a Frontotemporal dementia | |
| 650 | 4 | |a Cyclin F | |
| 650 | 4 | |a TDP-43 | |
| 650 | 4 | |a Ubiquitylation | |
| 650 | 4 | |a Aggregation | |
| 700 | 1 | |a Yang, Shu |e verfasserin |4 aut | |
| 700 | 1 | |a Farrawell, Natalie E. |e verfasserin |4 aut | |
| 700 | 1 | |a Jagaraj, Cyril J. |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Flora |e verfasserin |4 aut | |
| 700 | 1 | |a Davidson, Jennilee M. |e verfasserin |4 aut | |
| 700 | 1 | |a Luu, Luan |e verfasserin |4 aut | |
| 700 | 1 | |a Redondo, Alberto G. |e verfasserin |4 aut | |
| 700 | 1 | |a Rábano, Alberto |e verfasserin |4 aut | |
| 700 | 1 | |a Borrego-Hernández, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Atkin, Julie D. |e verfasserin |4 aut | |
| 700 | 1 | |a Morsch, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Blair, Ian P. |e verfasserin |4 aut | |
| 700 | 1 | |a Yerbury, Justin J. |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, Roger |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Albert |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Neurobiology of disease |d [Amsterdam] : Elsevier, 1994 |g 167 |h Online-Ressource |w (DE-627)268125414 |w (DE-600)1471408-5 |w (DE-576)27234947X |x 1095-953X |7 nnns |
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2022 |
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2022 |
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10.1016/j.nbd.2022.105673 doi (DE-627)ELV007613628 (ELSEVIER)S0969-9961(22)00064-X DE-627 ger DE-627 rda eng 610 570 DE-600 44.90 bkl Rayner, Stephanie L. verfasserin aut TDP-43 is a ubiquitylation substrate of the SCF 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons in the brain and spinal cord. ALS and frontotemporal dementia (FTD) are overlapping diseases with shared pathological features. Affected neurons of people with ALS and FTD typically contain ubiquitin-immunoreactive inclusions, of which TDP-43 (Tar DNA-binding protein of 43 kDa) is a major component. However, what triggers the formation of these abnormal TDP-43 inclusions is unclear. Previously, we identified CCNF mutations in cohorts of familial and sporadic cases of ALS and FTD. CCNF encodes cyclin F, the substrate-binding component of a multiprotein E3 ubiquitin ligase complex that ubiquitylates and subsequently directs a set of protein substrates for proteasomal degradation. Here, we explored the relationship between cyclin F and TDP-43.Methods: We used a series of complementary biochemical approaches including immunoprecipitations, in vitro ubiquitylation assays, immunofluorescence imaging and immunocytochemistry. Unpaired student t-tests were used to determine statistical significance of the results.Results: In this study, we demonstrate that that the SCFcyclin F complex directly mediates the poly-ubiquitylation of TDP-43. Importantly, we demonstrate that cyclin F bearing the pathogenic ALS/FTD mutation, S621G, leads to aberrant ubiquitylation of TDP-43 as well as the accumulation of K48-ubiquitylated TDP-43 in neuron-like cells. Furthermore, we demonstrate that a patient carrying the ALS/FTD cyclin FS195R mutation displayed skein-like cytoplasmic TDP-43 aggregates, implying abnormal TDP-43 degradation in a CCNF mutation bearing patient.Conclusion: In summary, this study reports a direct ubiquitylation mechanism for TDP-43, revealing important insights into the regulation of cyclin F-mediated TDP-43 turnover and clues towards understanding the molecular origins of the ubiquitylated TDP-43 inclusions that are the hallmark pathological feature in ALS and FTD. Amyotrophic lateral sclerosis Frontotemporal dementia Cyclin F TDP-43 Ubiquitylation Aggregation Yang, Shu verfasserin aut Farrawell, Natalie E. verfasserin aut Jagaraj, Cyril J. verfasserin aut Cheng, Flora verfasserin aut Davidson, Jennilee M. verfasserin aut Luu, Luan verfasserin aut Redondo, Alberto G. verfasserin aut Rábano, Alberto verfasserin aut Borrego-Hernández, Daniel verfasserin aut Atkin, Julie D. verfasserin aut Morsch, Marco verfasserin aut Blair, Ian P. verfasserin aut Yerbury, Justin J. verfasserin aut Chung, Roger verfasserin aut Lee, Albert verfasserin aut Enthalten in Neurobiology of disease [Amsterdam] : Elsevier, 1994 167 Online-Ressource (DE-627)268125414 (DE-600)1471408-5 (DE-576)27234947X 1095-953X nnns volume:167 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 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_4338 GBV_ILN_4367 GBV_ILN_4700 44.90 Neurologie AR 167 |
| spelling |
10.1016/j.nbd.2022.105673 doi (DE-627)ELV007613628 (ELSEVIER)S0969-9961(22)00064-X DE-627 ger DE-627 rda eng 610 570 DE-600 44.90 bkl Rayner, Stephanie L. verfasserin aut TDP-43 is a ubiquitylation substrate of the SCF 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons in the brain and spinal cord. ALS and frontotemporal dementia (FTD) are overlapping diseases with shared pathological features. Affected neurons of people with ALS and FTD typically contain ubiquitin-immunoreactive inclusions, of which TDP-43 (Tar DNA-binding protein of 43 kDa) is a major component. However, what triggers the formation of these abnormal TDP-43 inclusions is unclear. Previously, we identified CCNF mutations in cohorts of familial and sporadic cases of ALS and FTD. CCNF encodes cyclin F, the substrate-binding component of a multiprotein E3 ubiquitin ligase complex that ubiquitylates and subsequently directs a set of protein substrates for proteasomal degradation. Here, we explored the relationship between cyclin F and TDP-43.Methods: We used a series of complementary biochemical approaches including immunoprecipitations, in vitro ubiquitylation assays, immunofluorescence imaging and immunocytochemistry. Unpaired student t-tests were used to determine statistical significance of the results.Results: In this study, we demonstrate that that the SCFcyclin F complex directly mediates the poly-ubiquitylation of TDP-43. Importantly, we demonstrate that cyclin F bearing the pathogenic ALS/FTD mutation, S621G, leads to aberrant ubiquitylation of TDP-43 as well as the accumulation of K48-ubiquitylated TDP-43 in neuron-like cells. Furthermore, we demonstrate that a patient carrying the ALS/FTD cyclin FS195R mutation displayed skein-like cytoplasmic TDP-43 aggregates, implying abnormal TDP-43 degradation in a CCNF mutation bearing patient.Conclusion: In summary, this study reports a direct ubiquitylation mechanism for TDP-43, revealing important insights into the regulation of cyclin F-mediated TDP-43 turnover and clues towards understanding the molecular origins of the ubiquitylated TDP-43 inclusions that are the hallmark pathological feature in ALS and FTD. Amyotrophic lateral sclerosis Frontotemporal dementia Cyclin F TDP-43 Ubiquitylation Aggregation Yang, Shu verfasserin aut Farrawell, Natalie E. verfasserin aut Jagaraj, Cyril J. verfasserin aut Cheng, Flora verfasserin aut Davidson, Jennilee M. verfasserin aut Luu, Luan verfasserin aut Redondo, Alberto G. verfasserin aut Rábano, Alberto verfasserin aut Borrego-Hernández, Daniel verfasserin aut Atkin, Julie D. verfasserin aut Morsch, Marco verfasserin aut Blair, Ian P. verfasserin aut Yerbury, Justin J. verfasserin aut Chung, Roger verfasserin aut Lee, Albert verfasserin aut Enthalten in Neurobiology of disease [Amsterdam] : Elsevier, 1994 167 Online-Ressource (DE-627)268125414 (DE-600)1471408-5 (DE-576)27234947X 1095-953X nnns volume:167 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 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_4338 GBV_ILN_4367 GBV_ILN_4700 44.90 Neurologie AR 167 |
| allfields_unstemmed |
10.1016/j.nbd.2022.105673 doi (DE-627)ELV007613628 (ELSEVIER)S0969-9961(22)00064-X DE-627 ger DE-627 rda eng 610 570 DE-600 44.90 bkl Rayner, Stephanie L. verfasserin aut TDP-43 is a ubiquitylation substrate of the SCF 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons in the brain and spinal cord. ALS and frontotemporal dementia (FTD) are overlapping diseases with shared pathological features. Affected neurons of people with ALS and FTD typically contain ubiquitin-immunoreactive inclusions, of which TDP-43 (Tar DNA-binding protein of 43 kDa) is a major component. However, what triggers the formation of these abnormal TDP-43 inclusions is unclear. Previously, we identified CCNF mutations in cohorts of familial and sporadic cases of ALS and FTD. CCNF encodes cyclin F, the substrate-binding component of a multiprotein E3 ubiquitin ligase complex that ubiquitylates and subsequently directs a set of protein substrates for proteasomal degradation. Here, we explored the relationship between cyclin F and TDP-43.Methods: We used a series of complementary biochemical approaches including immunoprecipitations, in vitro ubiquitylation assays, immunofluorescence imaging and immunocytochemistry. Unpaired student t-tests were used to determine statistical significance of the results.Results: In this study, we demonstrate that that the SCFcyclin F complex directly mediates the poly-ubiquitylation of TDP-43. Importantly, we demonstrate that cyclin F bearing the pathogenic ALS/FTD mutation, S621G, leads to aberrant ubiquitylation of TDP-43 as well as the accumulation of K48-ubiquitylated TDP-43 in neuron-like cells. Furthermore, we demonstrate that a patient carrying the ALS/FTD cyclin FS195R mutation displayed skein-like cytoplasmic TDP-43 aggregates, implying abnormal TDP-43 degradation in a CCNF mutation bearing patient.Conclusion: In summary, this study reports a direct ubiquitylation mechanism for TDP-43, revealing important insights into the regulation of cyclin F-mediated TDP-43 turnover and clues towards understanding the molecular origins of the ubiquitylated TDP-43 inclusions that are the hallmark pathological feature in ALS and FTD. Amyotrophic lateral sclerosis Frontotemporal dementia Cyclin F TDP-43 Ubiquitylation Aggregation Yang, Shu verfasserin aut Farrawell, Natalie E. verfasserin aut Jagaraj, Cyril J. verfasserin aut Cheng, Flora verfasserin aut Davidson, Jennilee M. verfasserin aut Luu, Luan verfasserin aut Redondo, Alberto G. verfasserin aut Rábano, Alberto verfasserin aut Borrego-Hernández, Daniel verfasserin aut Atkin, Julie D. verfasserin aut Morsch, Marco verfasserin aut Blair, Ian P. verfasserin aut Yerbury, Justin J. verfasserin aut Chung, Roger verfasserin aut Lee, Albert verfasserin aut Enthalten in Neurobiology of disease [Amsterdam] : Elsevier, 1994 167 Online-Ressource (DE-627)268125414 (DE-600)1471408-5 (DE-576)27234947X 1095-953X nnns volume:167 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 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_4338 GBV_ILN_4367 GBV_ILN_4700 44.90 Neurologie AR 167 |
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10.1016/j.nbd.2022.105673 doi (DE-627)ELV007613628 (ELSEVIER)S0969-9961(22)00064-X DE-627 ger DE-627 rda eng 610 570 DE-600 44.90 bkl Rayner, Stephanie L. verfasserin aut TDP-43 is a ubiquitylation substrate of the SCF 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons in the brain and spinal cord. ALS and frontotemporal dementia (FTD) are overlapping diseases with shared pathological features. Affected neurons of people with ALS and FTD typically contain ubiquitin-immunoreactive inclusions, of which TDP-43 (Tar DNA-binding protein of 43 kDa) is a major component. However, what triggers the formation of these abnormal TDP-43 inclusions is unclear. Previously, we identified CCNF mutations in cohorts of familial and sporadic cases of ALS and FTD. CCNF encodes cyclin F, the substrate-binding component of a multiprotein E3 ubiquitin ligase complex that ubiquitylates and subsequently directs a set of protein substrates for proteasomal degradation. Here, we explored the relationship between cyclin F and TDP-43.Methods: We used a series of complementary biochemical approaches including immunoprecipitations, in vitro ubiquitylation assays, immunofluorescence imaging and immunocytochemistry. Unpaired student t-tests were used to determine statistical significance of the results.Results: In this study, we demonstrate that that the SCFcyclin F complex directly mediates the poly-ubiquitylation of TDP-43. Importantly, we demonstrate that cyclin F bearing the pathogenic ALS/FTD mutation, S621G, leads to aberrant ubiquitylation of TDP-43 as well as the accumulation of K48-ubiquitylated TDP-43 in neuron-like cells. Furthermore, we demonstrate that a patient carrying the ALS/FTD cyclin FS195R mutation displayed skein-like cytoplasmic TDP-43 aggregates, implying abnormal TDP-43 degradation in a CCNF mutation bearing patient.Conclusion: In summary, this study reports a direct ubiquitylation mechanism for TDP-43, revealing important insights into the regulation of cyclin F-mediated TDP-43 turnover and clues towards understanding the molecular origins of the ubiquitylated TDP-43 inclusions that are the hallmark pathological feature in ALS and FTD. Amyotrophic lateral sclerosis Frontotemporal dementia Cyclin F TDP-43 Ubiquitylation Aggregation Yang, Shu verfasserin aut Farrawell, Natalie E. verfasserin aut Jagaraj, Cyril J. verfasserin aut Cheng, Flora verfasserin aut Davidson, Jennilee M. verfasserin aut Luu, Luan verfasserin aut Redondo, Alberto G. verfasserin aut Rábano, Alberto verfasserin aut Borrego-Hernández, Daniel verfasserin aut Atkin, Julie D. verfasserin aut Morsch, Marco verfasserin aut Blair, Ian P. verfasserin aut Yerbury, Justin J. verfasserin aut Chung, Roger verfasserin aut Lee, Albert verfasserin aut Enthalten in Neurobiology of disease [Amsterdam] : Elsevier, 1994 167 Online-Ressource (DE-627)268125414 (DE-600)1471408-5 (DE-576)27234947X 1095-953X nnns volume:167 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 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_4338 GBV_ILN_4367 GBV_ILN_4700 44.90 Neurologie AR 167 |
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10.1016/j.nbd.2022.105673 doi (DE-627)ELV007613628 (ELSEVIER)S0969-9961(22)00064-X DE-627 ger DE-627 rda eng 610 570 DE-600 44.90 bkl Rayner, Stephanie L. verfasserin aut TDP-43 is a ubiquitylation substrate of the SCF 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons in the brain and spinal cord. ALS and frontotemporal dementia (FTD) are overlapping diseases with shared pathological features. Affected neurons of people with ALS and FTD typically contain ubiquitin-immunoreactive inclusions, of which TDP-43 (Tar DNA-binding protein of 43 kDa) is a major component. However, what triggers the formation of these abnormal TDP-43 inclusions is unclear. Previously, we identified CCNF mutations in cohorts of familial and sporadic cases of ALS and FTD. CCNF encodes cyclin F, the substrate-binding component of a multiprotein E3 ubiquitin ligase complex that ubiquitylates and subsequently directs a set of protein substrates for proteasomal degradation. Here, we explored the relationship between cyclin F and TDP-43.Methods: We used a series of complementary biochemical approaches including immunoprecipitations, in vitro ubiquitylation assays, immunofluorescence imaging and immunocytochemistry. Unpaired student t-tests were used to determine statistical significance of the results.Results: In this study, we demonstrate that that the SCFcyclin F complex directly mediates the poly-ubiquitylation of TDP-43. Importantly, we demonstrate that cyclin F bearing the pathogenic ALS/FTD mutation, S621G, leads to aberrant ubiquitylation of TDP-43 as well as the accumulation of K48-ubiquitylated TDP-43 in neuron-like cells. Furthermore, we demonstrate that a patient carrying the ALS/FTD cyclin FS195R mutation displayed skein-like cytoplasmic TDP-43 aggregates, implying abnormal TDP-43 degradation in a CCNF mutation bearing patient.Conclusion: In summary, this study reports a direct ubiquitylation mechanism for TDP-43, revealing important insights into the regulation of cyclin F-mediated TDP-43 turnover and clues towards understanding the molecular origins of the ubiquitylated TDP-43 inclusions that are the hallmark pathological feature in ALS and FTD. Amyotrophic lateral sclerosis Frontotemporal dementia Cyclin F TDP-43 Ubiquitylation Aggregation Yang, Shu verfasserin aut Farrawell, Natalie E. verfasserin aut Jagaraj, Cyril J. verfasserin aut Cheng, Flora verfasserin aut Davidson, Jennilee M. verfasserin aut Luu, Luan verfasserin aut Redondo, Alberto G. verfasserin aut Rábano, Alberto verfasserin aut Borrego-Hernández, Daniel verfasserin aut Atkin, Julie D. verfasserin aut Morsch, Marco verfasserin aut Blair, Ian P. verfasserin aut Yerbury, Justin J. verfasserin aut Chung, Roger verfasserin aut Lee, Albert verfasserin aut Enthalten in Neurobiology of disease [Amsterdam] : Elsevier, 1994 167 Online-Ressource (DE-627)268125414 (DE-600)1471408-5 (DE-576)27234947X 1095-953X nnns volume:167 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 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_4338 GBV_ILN_4367 GBV_ILN_4700 44.90 Neurologie AR 167 |
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Enthalten in Neurobiology of disease 167 volume:167 |
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Rayner, Stephanie L. @@aut@@ Yang, Shu @@aut@@ Farrawell, Natalie E. @@aut@@ Jagaraj, Cyril J. @@aut@@ Cheng, Flora @@aut@@ Davidson, Jennilee M. @@aut@@ Luu, Luan @@aut@@ Redondo, Alberto G. @@aut@@ Rábano, Alberto @@aut@@ Borrego-Hernández, Daniel @@aut@@ Atkin, Julie D. @@aut@@ Morsch, Marco @@aut@@ Blair, Ian P. @@aut@@ Yerbury, Justin J. @@aut@@ Chung, Roger @@aut@@ Lee, Albert @@aut@@ |
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2022-01-01T00:00:00Z |
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Rayner, Stephanie L. Yang, Shu Farrawell, Natalie E. Jagaraj, Cyril J. Cheng, Flora Davidson, Jennilee M. Luu, Luan Redondo, Alberto G. Rábano, Alberto Borrego-Hernández, Daniel Atkin, Julie D. Morsch, Marco Blair, Ian P. Yerbury, Justin J. Chung, Roger Lee, Albert |
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tdp-43 is a ubiquitylation substrate of the scf |
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TDP-43 is a ubiquitylation substrate of the SCF |
| abstract |
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons in the brain and spinal cord. ALS and frontotemporal dementia (FTD) are overlapping diseases with shared pathological features. Affected neurons of people with ALS and FTD typically contain ubiquitin-immunoreactive inclusions, of which TDP-43 (Tar DNA-binding protein of 43 kDa) is a major component. However, what triggers the formation of these abnormal TDP-43 inclusions is unclear. Previously, we identified CCNF mutations in cohorts of familial and sporadic cases of ALS and FTD. CCNF encodes cyclin F, the substrate-binding component of a multiprotein E3 ubiquitin ligase complex that ubiquitylates and subsequently directs a set of protein substrates for proteasomal degradation. Here, we explored the relationship between cyclin F and TDP-43.Methods: We used a series of complementary biochemical approaches including immunoprecipitations, in vitro ubiquitylation assays, immunofluorescence imaging and immunocytochemistry. Unpaired student t-tests were used to determine statistical significance of the results.Results: In this study, we demonstrate that that the SCFcyclin F complex directly mediates the poly-ubiquitylation of TDP-43. Importantly, we demonstrate that cyclin F bearing the pathogenic ALS/FTD mutation, S621G, leads to aberrant ubiquitylation of TDP-43 as well as the accumulation of K48-ubiquitylated TDP-43 in neuron-like cells. Furthermore, we demonstrate that a patient carrying the ALS/FTD cyclin FS195R mutation displayed skein-like cytoplasmic TDP-43 aggregates, implying abnormal TDP-43 degradation in a CCNF mutation bearing patient.Conclusion: In summary, this study reports a direct ubiquitylation mechanism for TDP-43, revealing important insights into the regulation of cyclin F-mediated TDP-43 turnover and clues towards understanding the molecular origins of the ubiquitylated TDP-43 inclusions that are the hallmark pathological feature in ALS and FTD. |
| abstractGer |
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons in the brain and spinal cord. ALS and frontotemporal dementia (FTD) are overlapping diseases with shared pathological features. Affected neurons of people with ALS and FTD typically contain ubiquitin-immunoreactive inclusions, of which TDP-43 (Tar DNA-binding protein of 43 kDa) is a major component. However, what triggers the formation of these abnormal TDP-43 inclusions is unclear. Previously, we identified CCNF mutations in cohorts of familial and sporadic cases of ALS and FTD. CCNF encodes cyclin F, the substrate-binding component of a multiprotein E3 ubiquitin ligase complex that ubiquitylates and subsequently directs a set of protein substrates for proteasomal degradation. Here, we explored the relationship between cyclin F and TDP-43.Methods: We used a series of complementary biochemical approaches including immunoprecipitations, in vitro ubiquitylation assays, immunofluorescence imaging and immunocytochemistry. Unpaired student t-tests were used to determine statistical significance of the results.Results: In this study, we demonstrate that that the SCFcyclin F complex directly mediates the poly-ubiquitylation of TDP-43. Importantly, we demonstrate that cyclin F bearing the pathogenic ALS/FTD mutation, S621G, leads to aberrant ubiquitylation of TDP-43 as well as the accumulation of K48-ubiquitylated TDP-43 in neuron-like cells. Furthermore, we demonstrate that a patient carrying the ALS/FTD cyclin FS195R mutation displayed skein-like cytoplasmic TDP-43 aggregates, implying abnormal TDP-43 degradation in a CCNF mutation bearing patient.Conclusion: In summary, this study reports a direct ubiquitylation mechanism for TDP-43, revealing important insights into the regulation of cyclin F-mediated TDP-43 turnover and clues towards understanding the molecular origins of the ubiquitylated TDP-43 inclusions that are the hallmark pathological feature in ALS and FTD. |
| abstract_unstemmed |
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons in the brain and spinal cord. ALS and frontotemporal dementia (FTD) are overlapping diseases with shared pathological features. Affected neurons of people with ALS and FTD typically contain ubiquitin-immunoreactive inclusions, of which TDP-43 (Tar DNA-binding protein of 43 kDa) is a major component. However, what triggers the formation of these abnormal TDP-43 inclusions is unclear. Previously, we identified CCNF mutations in cohorts of familial and sporadic cases of ALS and FTD. CCNF encodes cyclin F, the substrate-binding component of a multiprotein E3 ubiquitin ligase complex that ubiquitylates and subsequently directs a set of protein substrates for proteasomal degradation. Here, we explored the relationship between cyclin F and TDP-43.Methods: We used a series of complementary biochemical approaches including immunoprecipitations, in vitro ubiquitylation assays, immunofluorescence imaging and immunocytochemistry. Unpaired student t-tests were used to determine statistical significance of the results.Results: In this study, we demonstrate that that the SCFcyclin F complex directly mediates the poly-ubiquitylation of TDP-43. Importantly, we demonstrate that cyclin F bearing the pathogenic ALS/FTD mutation, S621G, leads to aberrant ubiquitylation of TDP-43 as well as the accumulation of K48-ubiquitylated TDP-43 in neuron-like cells. Furthermore, we demonstrate that a patient carrying the ALS/FTD cyclin FS195R mutation displayed skein-like cytoplasmic TDP-43 aggregates, implying abnormal TDP-43 degradation in a CCNF mutation bearing patient.Conclusion: In summary, this study reports a direct ubiquitylation mechanism for TDP-43, revealing important insights into the regulation of cyclin F-mediated TDP-43 turnover and clues towards understanding the molecular origins of the ubiquitylated TDP-43 inclusions that are the hallmark pathological feature in ALS and FTD. |
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Yang, Shu Farrawell, Natalie E. Jagaraj, Cyril J. Cheng, Flora Davidson, Jennilee M. Luu, Luan Redondo, Alberto G. Rábano, Alberto Borrego-Hernández, Daniel Atkin, Julie D. Morsch, Marco Blair, Ian P. Yerbury, Justin J. Chung, Roger Lee, Albert |
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| score |
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