Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of $ PrP^{Sc} $ and Targeting $ PrP^{Sc} $ for Lysosomal Degradation
Abstract $ PrP^{Sc} $ is an infectious and disease-specific conformer of the prion protein, which accumulation in the CNS underlies the pathology of prion diseases. $ PrP^{Sc} $ replicates by binding to the cellular conformer of the prion protein ($ PrP^{C} $) expressed by host cells and rendering i...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Pankiewicz, Joanna E. [verfasserIn] Sanchez, Sandrine [verfasserIn] Kirshenbaum, Kent [verfasserIn] Kascsak, Regina B. [verfasserIn] Kascsak, Richard J. [verfasserIn] Sadowski, Martin J. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2018 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Molecular neurobiology - Totowa, NJ : Humana Press, 1987, 56(2018), 3 vom: 09. Juli, Seite 2073-2091 |
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| Übergeordnetes Werk: |
volume:56 ; year:2018 ; number:3 ; day:09 ; month:07 ; pages:2073-2091 |
| Links: |
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| DOI / URN: |
10.1007/s12035-018-1208-4 |
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| Katalog-ID: |
SPR023985313 |
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| 100 | 1 | |a Pankiewicz, Joanna E. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of $ PrP^{Sc} $ and Targeting $ PrP^{Sc} $ for Lysosomal Degradation |
| 264 | 1 | |c 2018 | |
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| 337 | |a Computermedien |b c |2 rdamedia | ||
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| 520 | |a Abstract $ PrP^{Sc} $ is an infectious and disease-specific conformer of the prion protein, which accumulation in the CNS underlies the pathology of prion diseases. $ PrP^{Sc} $ replicates by binding to the cellular conformer of the prion protein ($ PrP^{C} $) expressed by host cells and rendering its secondary structure a likeness of itself. $ PrP^{C} $ is a plasma membrane anchored protein, which constitutively recirculates between the cell surface and the endocytic compartment. Since $ PrP^{Sc} $ engages $ PrP^{C} $ along this trafficking pathway, its replication process is often referred to as “recycling propagation.” Certain monoclonal antibodies (mAbs) directed against prion protein can abrogate the presence of $ PrP^{Sc} $ from prion-infected cells. However, the precise mechanism(s) underlying their therapeutic propensities remains obscure. Using N2A murine neuroblastoma cell line stably infected with 22L mouse-adapted scrapie strain (N2A/22L), we investigated here the modus operandi of the 6D11 clone, which was raised against the $ PrP^{Sc} $ conformer and has been shown to permanently clear prion-infected cells from $ PrP^{Sc} $ presence. We determined that 6D11 mAb engages and sequesters $ PrP^{C} $ and $ PrP^{Sc} $ at the cell surface. $ PrP^{C} $/6D11 and $ PrP^{Sc} $/6D11 complexes are then endocytosed from the plasma membrane and are directed to lysosomes, therefore precluding recirculation of nascent $ PrP^{Sc} $ back to the cell surface. Targeting $ PrP^{Sc} $ by 6D11 mAb to the lysosomal compartment facilitates its proteolysis and eventually shifts the balance between $ PrP^{Sc} $ formation and degradation. Ongoing translation of $ PrP^{C} $ allows maintaining the steady-state level of prion protein within the cells, which was not depleted under 6D11 mAb treatment. Our findings demonstrate that through disrupting recycling propagation of $ PrP^{Sc} $ and promoting its degradation, 6D11 mAb restores cellular proteostasis of prion protein. | ||
| 650 | 4 | |a Endo-lysosomal system |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Proteostasis |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Monoclonal antibody |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Passive immunization |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Prion protein |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a PrP |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a conformer |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Recycling propagation |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Sanchez, Sandrine |e verfasserin |4 aut | |
| 700 | 1 | |a Kirshenbaum, Kent |e verfasserin |4 aut | |
| 700 | 1 | |a Kascsak, Regina B. |e verfasserin |4 aut | |
| 700 | 1 | |a Kascsak, Richard J. |e verfasserin |4 aut | |
| 700 | 1 | |a Sadowski, Martin J. |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecular neurobiology |d Totowa, NJ : Humana Press, 1987 |g 56(2018), 3 vom: 09. Juli, Seite 2073-2091 |w (DE-627)34858444X |w (DE-600)2079384-4 |x 1559-1182 |7 nnns |
| 773 | 1 | 8 | |g volume:56 |g year:2018 |g number:3 |g day:09 |g month:07 |g pages:2073-2091 |
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| 912 | |a GBV_ILN_2064 | ||
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10.1007/s12035-018-1208-4 doi (DE-627)SPR023985313 (SPR)s12035-018-1208-4-e DE-627 ger DE-627 rakwb eng 610 570 ASE 44.90 bkl Pankiewicz, Joanna E. verfasserin aut Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of $ PrP^{Sc} $ and Targeting $ PrP^{Sc} $ for Lysosomal Degradation 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract $ PrP^{Sc} $ is an infectious and disease-specific conformer of the prion protein, which accumulation in the CNS underlies the pathology of prion diseases. $ PrP^{Sc} $ replicates by binding to the cellular conformer of the prion protein ($ PrP^{C} $) expressed by host cells and rendering its secondary structure a likeness of itself. $ PrP^{C} $ is a plasma membrane anchored protein, which constitutively recirculates between the cell surface and the endocytic compartment. Since $ PrP^{Sc} $ engages $ PrP^{C} $ along this trafficking pathway, its replication process is often referred to as “recycling propagation.” Certain monoclonal antibodies (mAbs) directed against prion protein can abrogate the presence of $ PrP^{Sc} $ from prion-infected cells. However, the precise mechanism(s) underlying their therapeutic propensities remains obscure. Using N2A murine neuroblastoma cell line stably infected with 22L mouse-adapted scrapie strain (N2A/22L), we investigated here the modus operandi of the 6D11 clone, which was raised against the $ PrP^{Sc} $ conformer and has been shown to permanently clear prion-infected cells from $ PrP^{Sc} $ presence. We determined that 6D11 mAb engages and sequesters $ PrP^{C} $ and $ PrP^{Sc} $ at the cell surface. $ PrP^{C} $/6D11 and $ PrP^{Sc} $/6D11 complexes are then endocytosed from the plasma membrane and are directed to lysosomes, therefore precluding recirculation of nascent $ PrP^{Sc} $ back to the cell surface. Targeting $ PrP^{Sc} $ by 6D11 mAb to the lysosomal compartment facilitates its proteolysis and eventually shifts the balance between $ PrP^{Sc} $ formation and degradation. Ongoing translation of $ PrP^{C} $ allows maintaining the steady-state level of prion protein within the cells, which was not depleted under 6D11 mAb treatment. Our findings demonstrate that through disrupting recycling propagation of $ PrP^{Sc} $ and promoting its degradation, 6D11 mAb restores cellular proteostasis of prion protein. Endo-lysosomal system (dpeaa)DE-He213 Proteostasis (dpeaa)DE-He213 Monoclonal antibody (dpeaa)DE-He213 Passive immunization (dpeaa)DE-He213 Prion protein (dpeaa)DE-He213 PrP (dpeaa)DE-He213 conformer (dpeaa)DE-He213 Recycling propagation (dpeaa)DE-He213 Sanchez, Sandrine verfasserin aut Kirshenbaum, Kent verfasserin aut Kascsak, Regina B. verfasserin aut Kascsak, Richard J. verfasserin aut Sadowski, Martin J. verfasserin aut Enthalten in Molecular neurobiology Totowa, NJ : Humana Press, 1987 56(2018), 3 vom: 09. Juli, Seite 2073-2091 (DE-627)34858444X (DE-600)2079384-4 1559-1182 nnns volume:56 year:2018 number:3 day:09 month:07 pages:2073-2091 https://dx.doi.org/10.1007/s12035-018-1208-4 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_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_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_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 56 2018 3 09 07 2073-2091 |
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10.1007/s12035-018-1208-4 doi (DE-627)SPR023985313 (SPR)s12035-018-1208-4-e DE-627 ger DE-627 rakwb eng 610 570 ASE 44.90 bkl Pankiewicz, Joanna E. verfasserin aut Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of $ PrP^{Sc} $ and Targeting $ PrP^{Sc} $ for Lysosomal Degradation 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract $ PrP^{Sc} $ is an infectious and disease-specific conformer of the prion protein, which accumulation in the CNS underlies the pathology of prion diseases. $ PrP^{Sc} $ replicates by binding to the cellular conformer of the prion protein ($ PrP^{C} $) expressed by host cells and rendering its secondary structure a likeness of itself. $ PrP^{C} $ is a plasma membrane anchored protein, which constitutively recirculates between the cell surface and the endocytic compartment. Since $ PrP^{Sc} $ engages $ PrP^{C} $ along this trafficking pathway, its replication process is often referred to as “recycling propagation.” Certain monoclonal antibodies (mAbs) directed against prion protein can abrogate the presence of $ PrP^{Sc} $ from prion-infected cells. However, the precise mechanism(s) underlying their therapeutic propensities remains obscure. Using N2A murine neuroblastoma cell line stably infected with 22L mouse-adapted scrapie strain (N2A/22L), we investigated here the modus operandi of the 6D11 clone, which was raised against the $ PrP^{Sc} $ conformer and has been shown to permanently clear prion-infected cells from $ PrP^{Sc} $ presence. We determined that 6D11 mAb engages and sequesters $ PrP^{C} $ and $ PrP^{Sc} $ at the cell surface. $ PrP^{C} $/6D11 and $ PrP^{Sc} $/6D11 complexes are then endocytosed from the plasma membrane and are directed to lysosomes, therefore precluding recirculation of nascent $ PrP^{Sc} $ back to the cell surface. Targeting $ PrP^{Sc} $ by 6D11 mAb to the lysosomal compartment facilitates its proteolysis and eventually shifts the balance between $ PrP^{Sc} $ formation and degradation. Ongoing translation of $ PrP^{C} $ allows maintaining the steady-state level of prion protein within the cells, which was not depleted under 6D11 mAb treatment. Our findings demonstrate that through disrupting recycling propagation of $ PrP^{Sc} $ and promoting its degradation, 6D11 mAb restores cellular proteostasis of prion protein. Endo-lysosomal system (dpeaa)DE-He213 Proteostasis (dpeaa)DE-He213 Monoclonal antibody (dpeaa)DE-He213 Passive immunization (dpeaa)DE-He213 Prion protein (dpeaa)DE-He213 PrP (dpeaa)DE-He213 conformer (dpeaa)DE-He213 Recycling propagation (dpeaa)DE-He213 Sanchez, Sandrine verfasserin aut Kirshenbaum, Kent verfasserin aut Kascsak, Regina B. verfasserin aut Kascsak, Richard J. verfasserin aut Sadowski, Martin J. verfasserin aut Enthalten in Molecular neurobiology Totowa, NJ : Humana Press, 1987 56(2018), 3 vom: 09. Juli, Seite 2073-2091 (DE-627)34858444X (DE-600)2079384-4 1559-1182 nnns volume:56 year:2018 number:3 day:09 month:07 pages:2073-2091 https://dx.doi.org/10.1007/s12035-018-1208-4 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_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_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_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 56 2018 3 09 07 2073-2091 |
| allfields_unstemmed |
10.1007/s12035-018-1208-4 doi (DE-627)SPR023985313 (SPR)s12035-018-1208-4-e DE-627 ger DE-627 rakwb eng 610 570 ASE 44.90 bkl Pankiewicz, Joanna E. verfasserin aut Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of $ PrP^{Sc} $ and Targeting $ PrP^{Sc} $ for Lysosomal Degradation 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract $ PrP^{Sc} $ is an infectious and disease-specific conformer of the prion protein, which accumulation in the CNS underlies the pathology of prion diseases. $ PrP^{Sc} $ replicates by binding to the cellular conformer of the prion protein ($ PrP^{C} $) expressed by host cells and rendering its secondary structure a likeness of itself. $ PrP^{C} $ is a plasma membrane anchored protein, which constitutively recirculates between the cell surface and the endocytic compartment. Since $ PrP^{Sc} $ engages $ PrP^{C} $ along this trafficking pathway, its replication process is often referred to as “recycling propagation.” Certain monoclonal antibodies (mAbs) directed against prion protein can abrogate the presence of $ PrP^{Sc} $ from prion-infected cells. However, the precise mechanism(s) underlying their therapeutic propensities remains obscure. Using N2A murine neuroblastoma cell line stably infected with 22L mouse-adapted scrapie strain (N2A/22L), we investigated here the modus operandi of the 6D11 clone, which was raised against the $ PrP^{Sc} $ conformer and has been shown to permanently clear prion-infected cells from $ PrP^{Sc} $ presence. We determined that 6D11 mAb engages and sequesters $ PrP^{C} $ and $ PrP^{Sc} $ at the cell surface. $ PrP^{C} $/6D11 and $ PrP^{Sc} $/6D11 complexes are then endocytosed from the plasma membrane and are directed to lysosomes, therefore precluding recirculation of nascent $ PrP^{Sc} $ back to the cell surface. Targeting $ PrP^{Sc} $ by 6D11 mAb to the lysosomal compartment facilitates its proteolysis and eventually shifts the balance between $ PrP^{Sc} $ formation and degradation. Ongoing translation of $ PrP^{C} $ allows maintaining the steady-state level of prion protein within the cells, which was not depleted under 6D11 mAb treatment. Our findings demonstrate that through disrupting recycling propagation of $ PrP^{Sc} $ and promoting its degradation, 6D11 mAb restores cellular proteostasis of prion protein. Endo-lysosomal system (dpeaa)DE-He213 Proteostasis (dpeaa)DE-He213 Monoclonal antibody (dpeaa)DE-He213 Passive immunization (dpeaa)DE-He213 Prion protein (dpeaa)DE-He213 PrP (dpeaa)DE-He213 conformer (dpeaa)DE-He213 Recycling propagation (dpeaa)DE-He213 Sanchez, Sandrine verfasserin aut Kirshenbaum, Kent verfasserin aut Kascsak, Regina B. verfasserin aut Kascsak, Richard J. verfasserin aut Sadowski, Martin J. verfasserin aut Enthalten in Molecular neurobiology Totowa, NJ : Humana Press, 1987 56(2018), 3 vom: 09. Juli, Seite 2073-2091 (DE-627)34858444X (DE-600)2079384-4 1559-1182 nnns volume:56 year:2018 number:3 day:09 month:07 pages:2073-2091 https://dx.doi.org/10.1007/s12035-018-1208-4 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_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_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_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 56 2018 3 09 07 2073-2091 |
| allfieldsGer |
10.1007/s12035-018-1208-4 doi (DE-627)SPR023985313 (SPR)s12035-018-1208-4-e DE-627 ger DE-627 rakwb eng 610 570 ASE 44.90 bkl Pankiewicz, Joanna E. verfasserin aut Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of $ PrP^{Sc} $ and Targeting $ PrP^{Sc} $ for Lysosomal Degradation 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract $ PrP^{Sc} $ is an infectious and disease-specific conformer of the prion protein, which accumulation in the CNS underlies the pathology of prion diseases. $ PrP^{Sc} $ replicates by binding to the cellular conformer of the prion protein ($ PrP^{C} $) expressed by host cells and rendering its secondary structure a likeness of itself. $ PrP^{C} $ is a plasma membrane anchored protein, which constitutively recirculates between the cell surface and the endocytic compartment. Since $ PrP^{Sc} $ engages $ PrP^{C} $ along this trafficking pathway, its replication process is often referred to as “recycling propagation.” Certain monoclonal antibodies (mAbs) directed against prion protein can abrogate the presence of $ PrP^{Sc} $ from prion-infected cells. However, the precise mechanism(s) underlying their therapeutic propensities remains obscure. Using N2A murine neuroblastoma cell line stably infected with 22L mouse-adapted scrapie strain (N2A/22L), we investigated here the modus operandi of the 6D11 clone, which was raised against the $ PrP^{Sc} $ conformer and has been shown to permanently clear prion-infected cells from $ PrP^{Sc} $ presence. We determined that 6D11 mAb engages and sequesters $ PrP^{C} $ and $ PrP^{Sc} $ at the cell surface. $ PrP^{C} $/6D11 and $ PrP^{Sc} $/6D11 complexes are then endocytosed from the plasma membrane and are directed to lysosomes, therefore precluding recirculation of nascent $ PrP^{Sc} $ back to the cell surface. Targeting $ PrP^{Sc} $ by 6D11 mAb to the lysosomal compartment facilitates its proteolysis and eventually shifts the balance between $ PrP^{Sc} $ formation and degradation. Ongoing translation of $ PrP^{C} $ allows maintaining the steady-state level of prion protein within the cells, which was not depleted under 6D11 mAb treatment. Our findings demonstrate that through disrupting recycling propagation of $ PrP^{Sc} $ and promoting its degradation, 6D11 mAb restores cellular proteostasis of prion protein. Endo-lysosomal system (dpeaa)DE-He213 Proteostasis (dpeaa)DE-He213 Monoclonal antibody (dpeaa)DE-He213 Passive immunization (dpeaa)DE-He213 Prion protein (dpeaa)DE-He213 PrP (dpeaa)DE-He213 conformer (dpeaa)DE-He213 Recycling propagation (dpeaa)DE-He213 Sanchez, Sandrine verfasserin aut Kirshenbaum, Kent verfasserin aut Kascsak, Regina B. verfasserin aut Kascsak, Richard J. verfasserin aut Sadowski, Martin J. verfasserin aut Enthalten in Molecular neurobiology Totowa, NJ : Humana Press, 1987 56(2018), 3 vom: 09. Juli, Seite 2073-2091 (DE-627)34858444X (DE-600)2079384-4 1559-1182 nnns volume:56 year:2018 number:3 day:09 month:07 pages:2073-2091 https://dx.doi.org/10.1007/s12035-018-1208-4 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_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_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_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 56 2018 3 09 07 2073-2091 |
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10.1007/s12035-018-1208-4 doi (DE-627)SPR023985313 (SPR)s12035-018-1208-4-e DE-627 ger DE-627 rakwb eng 610 570 ASE 44.90 bkl Pankiewicz, Joanna E. verfasserin aut Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of $ PrP^{Sc} $ and Targeting $ PrP^{Sc} $ for Lysosomal Degradation 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract $ PrP^{Sc} $ is an infectious and disease-specific conformer of the prion protein, which accumulation in the CNS underlies the pathology of prion diseases. $ PrP^{Sc} $ replicates by binding to the cellular conformer of the prion protein ($ PrP^{C} $) expressed by host cells and rendering its secondary structure a likeness of itself. $ PrP^{C} $ is a plasma membrane anchored protein, which constitutively recirculates between the cell surface and the endocytic compartment. Since $ PrP^{Sc} $ engages $ PrP^{C} $ along this trafficking pathway, its replication process is often referred to as “recycling propagation.” Certain monoclonal antibodies (mAbs) directed against prion protein can abrogate the presence of $ PrP^{Sc} $ from prion-infected cells. However, the precise mechanism(s) underlying their therapeutic propensities remains obscure. Using N2A murine neuroblastoma cell line stably infected with 22L mouse-adapted scrapie strain (N2A/22L), we investigated here the modus operandi of the 6D11 clone, which was raised against the $ PrP^{Sc} $ conformer and has been shown to permanently clear prion-infected cells from $ PrP^{Sc} $ presence. We determined that 6D11 mAb engages and sequesters $ PrP^{C} $ and $ PrP^{Sc} $ at the cell surface. $ PrP^{C} $/6D11 and $ PrP^{Sc} $/6D11 complexes are then endocytosed from the plasma membrane and are directed to lysosomes, therefore precluding recirculation of nascent $ PrP^{Sc} $ back to the cell surface. Targeting $ PrP^{Sc} $ by 6D11 mAb to the lysosomal compartment facilitates its proteolysis and eventually shifts the balance between $ PrP^{Sc} $ formation and degradation. Ongoing translation of $ PrP^{C} $ allows maintaining the steady-state level of prion protein within the cells, which was not depleted under 6D11 mAb treatment. Our findings demonstrate that through disrupting recycling propagation of $ PrP^{Sc} $ and promoting its degradation, 6D11 mAb restores cellular proteostasis of prion protein. Endo-lysosomal system (dpeaa)DE-He213 Proteostasis (dpeaa)DE-He213 Monoclonal antibody (dpeaa)DE-He213 Passive immunization (dpeaa)DE-He213 Prion protein (dpeaa)DE-He213 PrP (dpeaa)DE-He213 conformer (dpeaa)DE-He213 Recycling propagation (dpeaa)DE-He213 Sanchez, Sandrine verfasserin aut Kirshenbaum, Kent verfasserin aut Kascsak, Regina B. verfasserin aut Kascsak, Richard J. verfasserin aut Sadowski, Martin J. verfasserin aut Enthalten in Molecular neurobiology Totowa, NJ : Humana Press, 1987 56(2018), 3 vom: 09. Juli, Seite 2073-2091 (DE-627)34858444X (DE-600)2079384-4 1559-1182 nnns volume:56 year:2018 number:3 day:09 month:07 pages:2073-2091 https://dx.doi.org/10.1007/s12035-018-1208-4 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_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_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_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 56 2018 3 09 07 2073-2091 |
| language |
English |
| source |
Enthalten in Molecular neurobiology 56(2018), 3 vom: 09. Juli, Seite 2073-2091 volume:56 year:2018 number:3 day:09 month:07 pages:2073-2091 |
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Enthalten in Molecular neurobiology 56(2018), 3 vom: 09. Juli, Seite 2073-2091 volume:56 year:2018 number:3 day:09 month:07 pages:2073-2091 |
| format_phy_str_mv |
Article |
| institution |
findex.gbv.de |
| topic_facet |
Endo-lysosomal system Proteostasis Monoclonal antibody Passive immunization Prion protein PrP conformer Recycling propagation |
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610 |
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false |
| container_title |
Molecular neurobiology |
| authorswithroles_txt_mv |
Pankiewicz, Joanna E. @@aut@@ Sanchez, Sandrine @@aut@@ Kirshenbaum, Kent @@aut@@ Kascsak, Regina B. @@aut@@ Kascsak, Richard J. @@aut@@ Sadowski, Martin J. @@aut@@ |
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2018-07-09T00:00:00Z |
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34858444X |
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3610 |
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SPR023985313 |
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englisch |
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|
| author |
Pankiewicz, Joanna E. |
| spellingShingle |
Pankiewicz, Joanna E. ddc 610 bkl 44.90 misc Endo-lysosomal system misc Proteostasis misc Monoclonal antibody misc Passive immunization misc Prion protein misc PrP misc conformer misc Recycling propagation Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of $ PrP^{Sc} $ and Targeting $ PrP^{Sc} $ for Lysosomal Degradation |
| authorStr |
Pankiewicz, Joanna E. |
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electronic Article |
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610 - Medicine & health 570 - Life sciences; biology |
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1559-1182 |
| topic_title |
610 570 ASE 44.90 bkl Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of $ PrP^{Sc} $ and Targeting $ PrP^{Sc} $ for Lysosomal Degradation Endo-lysosomal system (dpeaa)DE-He213 Proteostasis (dpeaa)DE-He213 Monoclonal antibody (dpeaa)DE-He213 Passive immunization (dpeaa)DE-He213 Prion protein (dpeaa)DE-He213 PrP (dpeaa)DE-He213 conformer (dpeaa)DE-He213 Recycling propagation (dpeaa)DE-He213 |
| topic |
ddc 610 bkl 44.90 misc Endo-lysosomal system misc Proteostasis misc Monoclonal antibody misc Passive immunization misc Prion protein misc PrP misc conformer misc Recycling propagation |
| topic_unstemmed |
ddc 610 bkl 44.90 misc Endo-lysosomal system misc Proteostasis misc Monoclonal antibody misc Passive immunization misc Prion protein misc PrP misc conformer misc Recycling propagation |
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ddc 610 bkl 44.90 misc Endo-lysosomal system misc Proteostasis misc Monoclonal antibody misc Passive immunization misc Prion protein misc PrP misc conformer misc Recycling propagation |
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Molecular neurobiology |
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610 - Medicine & health 570 - Life sciences; biology |
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Molecular neurobiology |
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(DE-627)34858444X (DE-600)2079384-4 |
| title |
Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of $ PrP^{Sc} $ and Targeting $ PrP^{Sc} $ for Lysosomal Degradation |
| ctrlnum |
(DE-627)SPR023985313 (SPR)s12035-018-1208-4-e |
| title_full |
Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of $ PrP^{Sc} $ and Targeting $ PrP^{Sc} $ for Lysosomal Degradation |
| author_sort |
Pankiewicz, Joanna E. |
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Molecular neurobiology |
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Molecular neurobiology |
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eng |
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600 - Technology 500 - Science |
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2018 |
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2073 |
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Pankiewicz, Joanna E. Sanchez, Sandrine Kirshenbaum, Kent Kascsak, Regina B. Kascsak, Richard J. Sadowski, Martin J. |
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610 570 ASE 44.90 bkl |
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Elektronische Aufsätze |
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Pankiewicz, Joanna E. |
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10.1007/s12035-018-1208-4 |
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610 570 |
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verfasserin |
| title_sort |
anti-prion protein antibody 6d11 restores cellular proteostasis of prion protein through disrupting recycling propagation of $ prp^{sc} $ and targeting $ prp^{sc} $ for lysosomal degradation |
| title_auth |
Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of $ PrP^{Sc} $ and Targeting $ PrP^{Sc} $ for Lysosomal Degradation |
| abstract |
Abstract $ PrP^{Sc} $ is an infectious and disease-specific conformer of the prion protein, which accumulation in the CNS underlies the pathology of prion diseases. $ PrP^{Sc} $ replicates by binding to the cellular conformer of the prion protein ($ PrP^{C} $) expressed by host cells and rendering its secondary structure a likeness of itself. $ PrP^{C} $ is a plasma membrane anchored protein, which constitutively recirculates between the cell surface and the endocytic compartment. Since $ PrP^{Sc} $ engages $ PrP^{C} $ along this trafficking pathway, its replication process is often referred to as “recycling propagation.” Certain monoclonal antibodies (mAbs) directed against prion protein can abrogate the presence of $ PrP^{Sc} $ from prion-infected cells. However, the precise mechanism(s) underlying their therapeutic propensities remains obscure. Using N2A murine neuroblastoma cell line stably infected with 22L mouse-adapted scrapie strain (N2A/22L), we investigated here the modus operandi of the 6D11 clone, which was raised against the $ PrP^{Sc} $ conformer and has been shown to permanently clear prion-infected cells from $ PrP^{Sc} $ presence. We determined that 6D11 mAb engages and sequesters $ PrP^{C} $ and $ PrP^{Sc} $ at the cell surface. $ PrP^{C} $/6D11 and $ PrP^{Sc} $/6D11 complexes are then endocytosed from the plasma membrane and are directed to lysosomes, therefore precluding recirculation of nascent $ PrP^{Sc} $ back to the cell surface. Targeting $ PrP^{Sc} $ by 6D11 mAb to the lysosomal compartment facilitates its proteolysis and eventually shifts the balance between $ PrP^{Sc} $ formation and degradation. Ongoing translation of $ PrP^{C} $ allows maintaining the steady-state level of prion protein within the cells, which was not depleted under 6D11 mAb treatment. Our findings demonstrate that through disrupting recycling propagation of $ PrP^{Sc} $ and promoting its degradation, 6D11 mAb restores cellular proteostasis of prion protein. |
| abstractGer |
Abstract $ PrP^{Sc} $ is an infectious and disease-specific conformer of the prion protein, which accumulation in the CNS underlies the pathology of prion diseases. $ PrP^{Sc} $ replicates by binding to the cellular conformer of the prion protein ($ PrP^{C} $) expressed by host cells and rendering its secondary structure a likeness of itself. $ PrP^{C} $ is a plasma membrane anchored protein, which constitutively recirculates between the cell surface and the endocytic compartment. Since $ PrP^{Sc} $ engages $ PrP^{C} $ along this trafficking pathway, its replication process is often referred to as “recycling propagation.” Certain monoclonal antibodies (mAbs) directed against prion protein can abrogate the presence of $ PrP^{Sc} $ from prion-infected cells. However, the precise mechanism(s) underlying their therapeutic propensities remains obscure. Using N2A murine neuroblastoma cell line stably infected with 22L mouse-adapted scrapie strain (N2A/22L), we investigated here the modus operandi of the 6D11 clone, which was raised against the $ PrP^{Sc} $ conformer and has been shown to permanently clear prion-infected cells from $ PrP^{Sc} $ presence. We determined that 6D11 mAb engages and sequesters $ PrP^{C} $ and $ PrP^{Sc} $ at the cell surface. $ PrP^{C} $/6D11 and $ PrP^{Sc} $/6D11 complexes are then endocytosed from the plasma membrane and are directed to lysosomes, therefore precluding recirculation of nascent $ PrP^{Sc} $ back to the cell surface. Targeting $ PrP^{Sc} $ by 6D11 mAb to the lysosomal compartment facilitates its proteolysis and eventually shifts the balance between $ PrP^{Sc} $ formation and degradation. Ongoing translation of $ PrP^{C} $ allows maintaining the steady-state level of prion protein within the cells, which was not depleted under 6D11 mAb treatment. Our findings demonstrate that through disrupting recycling propagation of $ PrP^{Sc} $ and promoting its degradation, 6D11 mAb restores cellular proteostasis of prion protein. |
| abstract_unstemmed |
Abstract $ PrP^{Sc} $ is an infectious and disease-specific conformer of the prion protein, which accumulation in the CNS underlies the pathology of prion diseases. $ PrP^{Sc} $ replicates by binding to the cellular conformer of the prion protein ($ PrP^{C} $) expressed by host cells and rendering its secondary structure a likeness of itself. $ PrP^{C} $ is a plasma membrane anchored protein, which constitutively recirculates between the cell surface and the endocytic compartment. Since $ PrP^{Sc} $ engages $ PrP^{C} $ along this trafficking pathway, its replication process is often referred to as “recycling propagation.” Certain monoclonal antibodies (mAbs) directed against prion protein can abrogate the presence of $ PrP^{Sc} $ from prion-infected cells. However, the precise mechanism(s) underlying their therapeutic propensities remains obscure. Using N2A murine neuroblastoma cell line stably infected with 22L mouse-adapted scrapie strain (N2A/22L), we investigated here the modus operandi of the 6D11 clone, which was raised against the $ PrP^{Sc} $ conformer and has been shown to permanently clear prion-infected cells from $ PrP^{Sc} $ presence. We determined that 6D11 mAb engages and sequesters $ PrP^{C} $ and $ PrP^{Sc} $ at the cell surface. $ PrP^{C} $/6D11 and $ PrP^{Sc} $/6D11 complexes are then endocytosed from the plasma membrane and are directed to lysosomes, therefore precluding recirculation of nascent $ PrP^{Sc} $ back to the cell surface. Targeting $ PrP^{Sc} $ by 6D11 mAb to the lysosomal compartment facilitates its proteolysis and eventually shifts the balance between $ PrP^{Sc} $ formation and degradation. Ongoing translation of $ PrP^{C} $ allows maintaining the steady-state level of prion protein within the cells, which was not depleted under 6D11 mAb treatment. Our findings demonstrate that through disrupting recycling propagation of $ PrP^{Sc} $ and promoting its degradation, 6D11 mAb restores cellular proteostasis of prion protein. |
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| title_short |
Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of $ PrP^{Sc} $ and Targeting $ PrP^{Sc} $ for Lysosomal Degradation |
| url |
https://dx.doi.org/10.1007/s12035-018-1208-4 |
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Sanchez, Sandrine Kirshenbaum, Kent Kascsak, Regina B. Kascsak, Richard J. Sadowski, Martin J. |
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Sanchez, Sandrine Kirshenbaum, Kent Kascsak, Regina B. Kascsak, Richard J. Sadowski, Martin J. |
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| doi_str |
10.1007/s12035-018-1208-4 |
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2024-07-03T22:46:43.181Z |
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|
| score |
7.401 |