Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy
Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly un...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Lee, Albert [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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| Anmerkung: |
© Springer International Publishing AG 2017 |
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| Übergeordnetes Werk: |
Enthalten in: Cellular and molecular life sciences - Cham (ZG) : Springer International Publishing AG, 1997, 75(2017), 2 vom: 29. Aug., Seite 335-354 |
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| Übergeordnetes Werk: |
volume:75 ; year:2017 ; number:2 ; day:29 ; month:08 ; pages:335-354 |
| Links: |
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| DOI / URN: |
10.1007/s00018-017-2632-8 |
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| Katalog-ID: |
SPR000178543 |
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| 100 | 1 | |a Lee, Albert |e verfasserin |0 (orcid)0000-0001-5156-0567 |4 aut | |
| 245 | 1 | 0 | |a Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy |
| 264 | 1 | |c 2017 | |
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| 500 | |a © Springer International Publishing AG 2017 | ||
| 520 | |a Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase ($ SCF^{cyclin F} $) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin $ F^{S621G} $ caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin $ F^{WT} $. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin $ F^{S621G} $-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin $ F^{S621G} $ revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin $ F^{S621G} $ disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. | ||
| 650 | 4 | |a Ubiquitylation |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Phosphorylation |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a CCNF |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Cyclin F |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Amyotrophic lateral sclerosis |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Frontotemporal dementia |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Motor neuron disease |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Rayner, Stephanie L. |4 aut | |
| 700 | 1 | |a Gwee, Serene S. L. |4 aut | |
| 700 | 1 | |a De Luca, Alana |4 aut | |
| 700 | 1 | |a Shahheydari, Hamideh |4 aut | |
| 700 | 1 | |a Sundaramoorthy, Vinod |4 aut | |
| 700 | 1 | |a Ragagnin, Audrey |4 aut | |
| 700 | 1 | |a Morsch, Marco |4 aut | |
| 700 | 1 | |a Radford, Rowan |4 aut | |
| 700 | 1 | |a Galper, Jasmin |4 aut | |
| 700 | 1 | |a Freckleton, Sarah |4 aut | |
| 700 | 1 | |a Shi, Bingyang |4 aut | |
| 700 | 1 | |a Walker, Adam K. |4 aut | |
| 700 | 1 | |a Don, Emily K. |4 aut | |
| 700 | 1 | |a Cole, Nicholas J. |4 aut | |
| 700 | 1 | |a Yang, Shu |4 aut | |
| 700 | 1 | |a Williams, Kelly L. |4 aut | |
| 700 | 1 | |a Yerbury, Justin J. |4 aut | |
| 700 | 1 | |a Blair, Ian P. |4 aut | |
| 700 | 1 | |a Atkin, Julie D. |4 aut | |
| 700 | 1 | |a Molloy, Mark P. |4 aut | |
| 700 | 1 | |a Chung, Roger S. |4 aut | |
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10.1007/s00018-017-2632-8 doi (DE-627)SPR000178543 (SPR)s00018-017-2632-8-e DE-627 ger DE-627 rakwb eng Lee, Albert verfasserin (orcid)0000-0001-5156-0567 aut Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing AG 2017 Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase ($ SCF^{cyclin F} $) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin $ F^{S621G} $ caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin $ F^{WT} $. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin $ F^{S621G} $-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin $ F^{S621G} $ revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin $ F^{S621G} $ disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. Ubiquitylation (dpeaa)DE-He213 Phosphorylation (dpeaa)DE-He213 CCNF (dpeaa)DE-He213 Cyclin F (dpeaa)DE-He213 Amyotrophic lateral sclerosis (dpeaa)DE-He213 Frontotemporal dementia (dpeaa)DE-He213 Motor neuron disease (dpeaa)DE-He213 Rayner, Stephanie L. aut Gwee, Serene S. L. aut De Luca, Alana aut Shahheydari, Hamideh aut Sundaramoorthy, Vinod aut Ragagnin, Audrey aut Morsch, Marco aut Radford, Rowan aut Galper, Jasmin aut Freckleton, Sarah aut Shi, Bingyang aut Walker, Adam K. aut Don, Emily K. aut Cole, Nicholas J. aut Yang, Shu aut Williams, Kelly L. aut Yerbury, Justin J. aut Blair, Ian P. aut Atkin, Julie D. aut Molloy, Mark P. aut Chung, Roger S. aut Enthalten in Cellular and molecular life sciences Cham (ZG) : Springer International Publishing AG, 1997 75(2017), 2 vom: 29. Aug., Seite 335-354 (DE-627)253390524 (DE-600)1458497-9 1420-9071 nnns volume:75 year:2017 number:2 day:29 month:08 pages:335-354 https://dx.doi.org/10.1007/s00018-017-2632-8 lizenzpflichtig 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_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_165 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 AR 75 2017 2 29 08 335-354 |
| spelling |
10.1007/s00018-017-2632-8 doi (DE-627)SPR000178543 (SPR)s00018-017-2632-8-e DE-627 ger DE-627 rakwb eng Lee, Albert verfasserin (orcid)0000-0001-5156-0567 aut Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing AG 2017 Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase ($ SCF^{cyclin F} $) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin $ F^{S621G} $ caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin $ F^{WT} $. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin $ F^{S621G} $-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin $ F^{S621G} $ revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin $ F^{S621G} $ disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. Ubiquitylation (dpeaa)DE-He213 Phosphorylation (dpeaa)DE-He213 CCNF (dpeaa)DE-He213 Cyclin F (dpeaa)DE-He213 Amyotrophic lateral sclerosis (dpeaa)DE-He213 Frontotemporal dementia (dpeaa)DE-He213 Motor neuron disease (dpeaa)DE-He213 Rayner, Stephanie L. aut Gwee, Serene S. L. aut De Luca, Alana aut Shahheydari, Hamideh aut Sundaramoorthy, Vinod aut Ragagnin, Audrey aut Morsch, Marco aut Radford, Rowan aut Galper, Jasmin aut Freckleton, Sarah aut Shi, Bingyang aut Walker, Adam K. aut Don, Emily K. aut Cole, Nicholas J. aut Yang, Shu aut Williams, Kelly L. aut Yerbury, Justin J. aut Blair, Ian P. aut Atkin, Julie D. aut Molloy, Mark P. aut Chung, Roger S. aut Enthalten in Cellular and molecular life sciences Cham (ZG) : Springer International Publishing AG, 1997 75(2017), 2 vom: 29. Aug., Seite 335-354 (DE-627)253390524 (DE-600)1458497-9 1420-9071 nnns volume:75 year:2017 number:2 day:29 month:08 pages:335-354 https://dx.doi.org/10.1007/s00018-017-2632-8 lizenzpflichtig 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_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_165 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 AR 75 2017 2 29 08 335-354 |
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10.1007/s00018-017-2632-8 doi (DE-627)SPR000178543 (SPR)s00018-017-2632-8-e DE-627 ger DE-627 rakwb eng Lee, Albert verfasserin (orcid)0000-0001-5156-0567 aut Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing AG 2017 Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase ($ SCF^{cyclin F} $) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin $ F^{S621G} $ caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin $ F^{WT} $. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin $ F^{S621G} $-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin $ F^{S621G} $ revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin $ F^{S621G} $ disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. Ubiquitylation (dpeaa)DE-He213 Phosphorylation (dpeaa)DE-He213 CCNF (dpeaa)DE-He213 Cyclin F (dpeaa)DE-He213 Amyotrophic lateral sclerosis (dpeaa)DE-He213 Frontotemporal dementia (dpeaa)DE-He213 Motor neuron disease (dpeaa)DE-He213 Rayner, Stephanie L. aut Gwee, Serene S. L. aut De Luca, Alana aut Shahheydari, Hamideh aut Sundaramoorthy, Vinod aut Ragagnin, Audrey aut Morsch, Marco aut Radford, Rowan aut Galper, Jasmin aut Freckleton, Sarah aut Shi, Bingyang aut Walker, Adam K. aut Don, Emily K. aut Cole, Nicholas J. aut Yang, Shu aut Williams, Kelly L. aut Yerbury, Justin J. aut Blair, Ian P. aut Atkin, Julie D. aut Molloy, Mark P. aut Chung, Roger S. aut Enthalten in Cellular and molecular life sciences Cham (ZG) : Springer International Publishing AG, 1997 75(2017), 2 vom: 29. Aug., Seite 335-354 (DE-627)253390524 (DE-600)1458497-9 1420-9071 nnns volume:75 year:2017 number:2 day:29 month:08 pages:335-354 https://dx.doi.org/10.1007/s00018-017-2632-8 lizenzpflichtig 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_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_165 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 AR 75 2017 2 29 08 335-354 |
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10.1007/s00018-017-2632-8 doi (DE-627)SPR000178543 (SPR)s00018-017-2632-8-e DE-627 ger DE-627 rakwb eng Lee, Albert verfasserin (orcid)0000-0001-5156-0567 aut Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing AG 2017 Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase ($ SCF^{cyclin F} $) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin $ F^{S621G} $ caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin $ F^{WT} $. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin $ F^{S621G} $-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin $ F^{S621G} $ revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin $ F^{S621G} $ disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. Ubiquitylation (dpeaa)DE-He213 Phosphorylation (dpeaa)DE-He213 CCNF (dpeaa)DE-He213 Cyclin F (dpeaa)DE-He213 Amyotrophic lateral sclerosis (dpeaa)DE-He213 Frontotemporal dementia (dpeaa)DE-He213 Motor neuron disease (dpeaa)DE-He213 Rayner, Stephanie L. aut Gwee, Serene S. L. aut De Luca, Alana aut Shahheydari, Hamideh aut Sundaramoorthy, Vinod aut Ragagnin, Audrey aut Morsch, Marco aut Radford, Rowan aut Galper, Jasmin aut Freckleton, Sarah aut Shi, Bingyang aut Walker, Adam K. aut Don, Emily K. aut Cole, Nicholas J. aut Yang, Shu aut Williams, Kelly L. aut Yerbury, Justin J. aut Blair, Ian P. aut Atkin, Julie D. aut Molloy, Mark P. aut Chung, Roger S. aut Enthalten in Cellular and molecular life sciences Cham (ZG) : Springer International Publishing AG, 1997 75(2017), 2 vom: 29. Aug., Seite 335-354 (DE-627)253390524 (DE-600)1458497-9 1420-9071 nnns volume:75 year:2017 number:2 day:29 month:08 pages:335-354 https://dx.doi.org/10.1007/s00018-017-2632-8 lizenzpflichtig 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_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_165 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 AR 75 2017 2 29 08 335-354 |
| allfieldsSound |
10.1007/s00018-017-2632-8 doi (DE-627)SPR000178543 (SPR)s00018-017-2632-8-e DE-627 ger DE-627 rakwb eng Lee, Albert verfasserin (orcid)0000-0001-5156-0567 aut Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing AG 2017 Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase ($ SCF^{cyclin F} $) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin $ F^{S621G} $ caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin $ F^{WT} $. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin $ F^{S621G} $-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin $ F^{S621G} $ revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin $ F^{S621G} $ disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. Ubiquitylation (dpeaa)DE-He213 Phosphorylation (dpeaa)DE-He213 CCNF (dpeaa)DE-He213 Cyclin F (dpeaa)DE-He213 Amyotrophic lateral sclerosis (dpeaa)DE-He213 Frontotemporal dementia (dpeaa)DE-He213 Motor neuron disease (dpeaa)DE-He213 Rayner, Stephanie L. aut Gwee, Serene S. L. aut De Luca, Alana aut Shahheydari, Hamideh aut Sundaramoorthy, Vinod aut Ragagnin, Audrey aut Morsch, Marco aut Radford, Rowan aut Galper, Jasmin aut Freckleton, Sarah aut Shi, Bingyang aut Walker, Adam K. aut Don, Emily K. aut Cole, Nicholas J. aut Yang, Shu aut Williams, Kelly L. aut Yerbury, Justin J. aut Blair, Ian P. aut Atkin, Julie D. aut Molloy, Mark P. aut Chung, Roger S. aut Enthalten in Cellular and molecular life sciences Cham (ZG) : Springer International Publishing AG, 1997 75(2017), 2 vom: 29. Aug., Seite 335-354 (DE-627)253390524 (DE-600)1458497-9 1420-9071 nnns volume:75 year:2017 number:2 day:29 month:08 pages:335-354 https://dx.doi.org/10.1007/s00018-017-2632-8 lizenzpflichtig 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_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_165 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 AR 75 2017 2 29 08 335-354 |
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Enthalten in Cellular and molecular life sciences 75(2017), 2 vom: 29. Aug., Seite 335-354 volume:75 year:2017 number:2 day:29 month:08 pages:335-354 |
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Enthalten in Cellular and molecular life sciences 75(2017), 2 vom: 29. Aug., Seite 335-354 volume:75 year:2017 number:2 day:29 month:08 pages:335-354 |
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Ubiquitylation Phosphorylation CCNF Cyclin F Amyotrophic lateral sclerosis Frontotemporal dementia Motor neuron disease |
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Lee, Albert @@aut@@ Rayner, Stephanie L. @@aut@@ Gwee, Serene S. L. @@aut@@ De Luca, Alana @@aut@@ Shahheydari, Hamideh @@aut@@ Sundaramoorthy, Vinod @@aut@@ Ragagnin, Audrey @@aut@@ Morsch, Marco @@aut@@ Radford, Rowan @@aut@@ Galper, Jasmin @@aut@@ Freckleton, Sarah @@aut@@ Shi, Bingyang @@aut@@ Walker, Adam K. @@aut@@ Don, Emily K. @@aut@@ Cole, Nicholas J. @@aut@@ Yang, Shu @@aut@@ Williams, Kelly L. @@aut@@ Yerbury, Justin J. @@aut@@ Blair, Ian P. @@aut@@ Atkin, Julie D. @@aut@@ Molloy, Mark P. @@aut@@ Chung, Roger S. @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR000178543</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230520004552.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201001s2017 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1007/s00018-017-2632-8</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR000178543</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s00018-017-2632-8-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">Lee, Albert</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0001-5156-0567</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2017</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">© Springer International Publishing AG 2017</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase ($ SCF^{cyclin F} $) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin $ F^{S621G} $ caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin $ F^{WT} $. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin $ F^{S621G} $-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin $ F^{S621G} $ revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin $ F^{S621G} $ disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Ubiquitylation</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Phosphorylation</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">CCNF</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cyclin F</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Amyotrophic lateral sclerosis</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Frontotemporal dementia</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Motor neuron disease</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Rayner, Stephanie L.</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Gwee, Serene S. 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|
| author |
Lee, Albert |
| spellingShingle |
Lee, Albert misc Ubiquitylation misc Phosphorylation misc CCNF misc Cyclin F misc Amyotrophic lateral sclerosis misc Frontotemporal dementia misc Motor neuron disease Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy |
| authorStr |
Lee, Albert |
| ppnlink_with_tag_str_mv |
@@773@@(DE-627)253390524 |
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Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy Ubiquitylation (dpeaa)DE-He213 Phosphorylation (dpeaa)DE-He213 CCNF (dpeaa)DE-He213 Cyclin F (dpeaa)DE-He213 Amyotrophic lateral sclerosis (dpeaa)DE-He213 Frontotemporal dementia (dpeaa)DE-He213 Motor neuron disease (dpeaa)DE-He213 |
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misc Ubiquitylation misc Phosphorylation misc CCNF misc Cyclin F misc Amyotrophic lateral sclerosis misc Frontotemporal dementia misc Motor neuron disease |
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misc Ubiquitylation misc Phosphorylation misc CCNF misc Cyclin F misc Amyotrophic lateral sclerosis misc Frontotemporal dementia misc Motor neuron disease |
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Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy |
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Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy |
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Lee, Albert Rayner, Stephanie L. Gwee, Serene S. L. De Luca, Alana Shahheydari, Hamideh Sundaramoorthy, Vinod Ragagnin, Audrey Morsch, Marco Radford, Rowan Galper, Jasmin Freckleton, Sarah Shi, Bingyang Walker, Adam K. Don, Emily K. Cole, Nicholas J. Yang, Shu Williams, Kelly L. Yerbury, Justin J. Blair, Ian P. Atkin, Julie D. Molloy, Mark P. Chung, Roger S. |
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pathogenic mutation in the als/ftd gene, ccnf, causes elevated lys48-linked ubiquitylation and defective autophagy |
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Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy |
| abstract |
Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase ($ SCF^{cyclin F} $) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin $ F^{S621G} $ caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin $ F^{WT} $. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin $ F^{S621G} $-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin $ F^{S621G} $ revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin $ F^{S621G} $ disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. © Springer International Publishing AG 2017 |
| abstractGer |
Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase ($ SCF^{cyclin F} $) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin $ F^{S621G} $ caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin $ F^{WT} $. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin $ F^{S621G} $-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin $ F^{S621G} $ revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin $ F^{S621G} $ disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. © Springer International Publishing AG 2017 |
| abstract_unstemmed |
Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase ($ SCF^{cyclin F} $) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin $ F^{S621G} $ caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin $ F^{WT} $. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin $ F^{S621G} $-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin $ F^{S621G} $ revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin $ F^{S621G} $ disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. © Springer International Publishing AG 2017 |
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Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy |
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| score |
7.400197 |