Molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene SNP
Abstract Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million Euro...
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Vogt, Johannes [verfasserIn] Yang, Jenq‐Wei [verfasserIn] Mobascher, Arian [verfasserIn] Cheng, Jin [verfasserIn] Li, Yunbo [verfasserIn] Liu, Xingfeng [verfasserIn] Baumgart, Jan [verfasserIn] Thalman, Carine [verfasserIn] Kirischuk, Sergei [verfasserIn] Unichenko, Petr [verfasserIn] Horta, Guilherme [verfasserIn] Radyushkin, Konstantin [verfasserIn] Stroh, Albrecht [verfasserIn] Richers, Sebastian [verfasserIn] Sahragard, Nassim [verfasserIn] Distler, Ute [verfasserIn] Tenzer, Stefan [verfasserIn] Qiao, Lianyong [verfasserIn] Lieb, Klaus [verfasserIn] Tüscher, Oliver [verfasserIn] Binder, Harald [verfasserIn] Ferreiros, Nerea [verfasserIn] Tegeder, Irmgard [verfasserIn] Morris, Andrew J [verfasserIn] Gropa, Sergiu [verfasserIn] Nürnberg, Peter [verfasserIn] Toliat, Mohammad R [verfasserIn] Winterer, Georg [verfasserIn] Luhmann, Heiko J [verfasserIn] Huai, Jisen [verfasserIn] Nitsch, Robert [verfasserIn] |
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E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2015 |
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© The Authors. Published under the terms of the CC BY 4.0 license 2015 |
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| Übergeordnetes Werk: |
Enthalten in: EMBO Molecular Medicine - Nature Publishing Group UK, 2023, 8(2015), 1 vom: 15. Dez., Seite 25-38 |
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| Übergeordnetes Werk: |
volume:8 ; year:2015 ; number:1 ; day:15 ; month:12 ; pages:25-38 |
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| DOI / URN: |
10.15252/emmm.201505677 |
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SPR05790751X |
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| 100 | 1 | |a Vogt, Johannes |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene SNP |
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| 500 | |a © The Authors. Published under the terms of the CC BY 4.0 license 2015 | ||
| 520 | |a Abstract Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐$ 1^{+/−} $ mice, which are animal correlates of human PRG‐$ 1^{+/mut} $ carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases. | ||
| 520 | |a Synopsis Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. The human PRG‐1 SNP (R345T), present in a monoallelic variant, abolished PRG‐1 function by impeding its ability for LPA internalization due to altered glycosylation.Monoallelic PRG‐1 deficiency affected cortical information processing, leading to decreased somatosensory filter function in rodents and humans, and impaired resilience during stress‐related behaviors, an endophenotype of psychiatric disorders.Pharmacological intervention specifically targeting phospholipid signaling rescued cortical somatosensory filter function to wild‐type levels, opening a new therapeutic perspective for stress‐related mental dysfunctions. | ||
| 520 | |a Graphical Abstract Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. | ||
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| 700 | 1 | |a Yang, Jenq‐Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Mobascher, Arian |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yunbo |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xingfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Baumgart, Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Thalman, Carine |e verfasserin |4 aut | |
| 700 | 1 | |a Kirischuk, Sergei |e verfasserin |4 aut | |
| 700 | 1 | |a Unichenko, Petr |e verfasserin |4 aut | |
| 700 | 1 | |a Horta, Guilherme |e verfasserin |4 aut | |
| 700 | 1 | |a Radyushkin, Konstantin |e verfasserin |4 aut | |
| 700 | 1 | |a Stroh, Albrecht |e verfasserin |4 aut | |
| 700 | 1 | |a Richers, Sebastian |e verfasserin |4 aut | |
| 700 | 1 | |a Sahragard, Nassim |e verfasserin |4 aut | |
| 700 | 1 | |a Distler, Ute |e verfasserin |4 aut | |
| 700 | 1 | |a Tenzer, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Qiao, Lianyong |e verfasserin |4 aut | |
| 700 | 1 | |a Lieb, Klaus |e verfasserin |4 aut | |
| 700 | 1 | |a Tüscher, Oliver |e verfasserin |4 aut | |
| 700 | 1 | |a Binder, Harald |e verfasserin |4 aut | |
| 700 | 1 | |a Ferreiros, Nerea |e verfasserin |4 aut | |
| 700 | 1 | |a Tegeder, Irmgard |e verfasserin |4 aut | |
| 700 | 1 | |a Morris, Andrew J |e verfasserin |4 aut | |
| 700 | 1 | |a Gropa, Sergiu |e verfasserin |4 aut | |
| 700 | 1 | |a Nürnberg, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Toliat, Mohammad R |e verfasserin |4 aut | |
| 700 | 1 | |a Winterer, Georg |e verfasserin |4 aut | |
| 700 | 1 | |a Luhmann, Heiko J |e verfasserin |4 aut | |
| 700 | 1 | |a Huai, Jisen |e verfasserin |4 aut | |
| 700 | 1 | |a Nitsch, Robert |e verfasserin |4 aut | |
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10.15252/emmm.201505677 doi (DE-627)SPR05790751X (SPR)emmm.201505677-e DE-627 ger DE-627 rakwb eng Vogt, Johannes verfasserin aut Molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene SNP 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors. Published under the terms of the CC BY 4.0 license 2015 Abstract Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐$ 1^{+/−} $ mice, which are animal correlates of human PRG‐$ 1^{+/mut} $ carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases. Synopsis Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. The human PRG‐1 SNP (R345T), present in a monoallelic variant, abolished PRG‐1 function by impeding its ability for LPA internalization due to altered glycosylation.Monoallelic PRG‐1 deficiency affected cortical information processing, leading to decreased somatosensory filter function in rodents and humans, and impaired resilience during stress‐related behaviors, an endophenotype of psychiatric disorders.Pharmacological intervention specifically targeting phospholipid signaling rescued cortical somatosensory filter function to wild‐type levels, opening a new therapeutic perspective for stress‐related mental dysfunctions. Graphical Abstract Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. bioactive phospholipids (dpeaa)DE-He213 cortical network (dpeaa)DE-He213 PRG‐1 (dpeaa)DE-He213 psychiatric disorders (dpeaa)DE-He213 synapse (dpeaa)DE-He213 Yang, Jenq‐Wei verfasserin aut Mobascher, Arian verfasserin aut Cheng, Jin verfasserin aut Li, Yunbo verfasserin aut Liu, Xingfeng verfasserin aut Baumgart, Jan verfasserin aut Thalman, Carine verfasserin aut Kirischuk, Sergei verfasserin aut Unichenko, Petr verfasserin aut Horta, Guilherme verfasserin aut Radyushkin, Konstantin verfasserin aut Stroh, Albrecht verfasserin aut Richers, Sebastian verfasserin aut Sahragard, Nassim verfasserin aut Distler, Ute verfasserin aut Tenzer, Stefan verfasserin aut Qiao, Lianyong verfasserin aut Lieb, Klaus verfasserin aut Tüscher, Oliver verfasserin aut Binder, Harald verfasserin aut Ferreiros, Nerea verfasserin aut Tegeder, Irmgard verfasserin aut Morris, Andrew J verfasserin aut Gropa, Sergiu verfasserin aut Nürnberg, Peter verfasserin aut Toliat, Mohammad R verfasserin aut Winterer, Georg verfasserin aut Luhmann, Heiko J verfasserin aut Huai, Jisen verfasserin aut Nitsch, Robert verfasserin aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 8(2015), 1 vom: 15. Dez., Seite 25-38 (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:8 year:2015 number:1 day:15 month:12 pages:25-38 https://dx.doi.org/10.15252/emmm.201505677 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_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_4367 GBV_ILN_4393 GBV_ILN_4700 AR 8 2015 1 15 12 25-38 |
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10.15252/emmm.201505677 doi (DE-627)SPR05790751X (SPR)emmm.201505677-e DE-627 ger DE-627 rakwb eng Vogt, Johannes verfasserin aut Molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene SNP 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors. Published under the terms of the CC BY 4.0 license 2015 Abstract Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐$ 1^{+/−} $ mice, which are animal correlates of human PRG‐$ 1^{+/mut} $ carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases. Synopsis Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. The human PRG‐1 SNP (R345T), present in a monoallelic variant, abolished PRG‐1 function by impeding its ability for LPA internalization due to altered glycosylation.Monoallelic PRG‐1 deficiency affected cortical information processing, leading to decreased somatosensory filter function in rodents and humans, and impaired resilience during stress‐related behaviors, an endophenotype of psychiatric disorders.Pharmacological intervention specifically targeting phospholipid signaling rescued cortical somatosensory filter function to wild‐type levels, opening a new therapeutic perspective for stress‐related mental dysfunctions. Graphical Abstract Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. bioactive phospholipids (dpeaa)DE-He213 cortical network (dpeaa)DE-He213 PRG‐1 (dpeaa)DE-He213 psychiatric disorders (dpeaa)DE-He213 synapse (dpeaa)DE-He213 Yang, Jenq‐Wei verfasserin aut Mobascher, Arian verfasserin aut Cheng, Jin verfasserin aut Li, Yunbo verfasserin aut Liu, Xingfeng verfasserin aut Baumgart, Jan verfasserin aut Thalman, Carine verfasserin aut Kirischuk, Sergei verfasserin aut Unichenko, Petr verfasserin aut Horta, Guilherme verfasserin aut Radyushkin, Konstantin verfasserin aut Stroh, Albrecht verfasserin aut Richers, Sebastian verfasserin aut Sahragard, Nassim verfasserin aut Distler, Ute verfasserin aut Tenzer, Stefan verfasserin aut Qiao, Lianyong verfasserin aut Lieb, Klaus verfasserin aut Tüscher, Oliver verfasserin aut Binder, Harald verfasserin aut Ferreiros, Nerea verfasserin aut Tegeder, Irmgard verfasserin aut Morris, Andrew J verfasserin aut Gropa, Sergiu verfasserin aut Nürnberg, Peter verfasserin aut Toliat, Mohammad R verfasserin aut Winterer, Georg verfasserin aut Luhmann, Heiko J verfasserin aut Huai, Jisen verfasserin aut Nitsch, Robert verfasserin aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 8(2015), 1 vom: 15. Dez., Seite 25-38 (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:8 year:2015 number:1 day:15 month:12 pages:25-38 https://dx.doi.org/10.15252/emmm.201505677 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_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_4367 GBV_ILN_4393 GBV_ILN_4700 AR 8 2015 1 15 12 25-38 |
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10.15252/emmm.201505677 doi (DE-627)SPR05790751X (SPR)emmm.201505677-e DE-627 ger DE-627 rakwb eng Vogt, Johannes verfasserin aut Molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene SNP 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors. Published under the terms of the CC BY 4.0 license 2015 Abstract Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐$ 1^{+/−} $ mice, which are animal correlates of human PRG‐$ 1^{+/mut} $ carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases. Synopsis Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. The human PRG‐1 SNP (R345T), present in a monoallelic variant, abolished PRG‐1 function by impeding its ability for LPA internalization due to altered glycosylation.Monoallelic PRG‐1 deficiency affected cortical information processing, leading to decreased somatosensory filter function in rodents and humans, and impaired resilience during stress‐related behaviors, an endophenotype of psychiatric disorders.Pharmacological intervention specifically targeting phospholipid signaling rescued cortical somatosensory filter function to wild‐type levels, opening a new therapeutic perspective for stress‐related mental dysfunctions. Graphical Abstract Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. bioactive phospholipids (dpeaa)DE-He213 cortical network (dpeaa)DE-He213 PRG‐1 (dpeaa)DE-He213 psychiatric disorders (dpeaa)DE-He213 synapse (dpeaa)DE-He213 Yang, Jenq‐Wei verfasserin aut Mobascher, Arian verfasserin aut Cheng, Jin verfasserin aut Li, Yunbo verfasserin aut Liu, Xingfeng verfasserin aut Baumgart, Jan verfasserin aut Thalman, Carine verfasserin aut Kirischuk, Sergei verfasserin aut Unichenko, Petr verfasserin aut Horta, Guilherme verfasserin aut Radyushkin, Konstantin verfasserin aut Stroh, Albrecht verfasserin aut Richers, Sebastian verfasserin aut Sahragard, Nassim verfasserin aut Distler, Ute verfasserin aut Tenzer, Stefan verfasserin aut Qiao, Lianyong verfasserin aut Lieb, Klaus verfasserin aut Tüscher, Oliver verfasserin aut Binder, Harald verfasserin aut Ferreiros, Nerea verfasserin aut Tegeder, Irmgard verfasserin aut Morris, Andrew J verfasserin aut Gropa, Sergiu verfasserin aut Nürnberg, Peter verfasserin aut Toliat, Mohammad R verfasserin aut Winterer, Georg verfasserin aut Luhmann, Heiko J verfasserin aut Huai, Jisen verfasserin aut Nitsch, Robert verfasserin aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 8(2015), 1 vom: 15. Dez., Seite 25-38 (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:8 year:2015 number:1 day:15 month:12 pages:25-38 https://dx.doi.org/10.15252/emmm.201505677 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_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_4367 GBV_ILN_4393 GBV_ILN_4700 AR 8 2015 1 15 12 25-38 |
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10.15252/emmm.201505677 doi (DE-627)SPR05790751X (SPR)emmm.201505677-e DE-627 ger DE-627 rakwb eng Vogt, Johannes verfasserin aut Molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene SNP 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors. Published under the terms of the CC BY 4.0 license 2015 Abstract Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐$ 1^{+/−} $ mice, which are animal correlates of human PRG‐$ 1^{+/mut} $ carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases. Synopsis Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. The human PRG‐1 SNP (R345T), present in a monoallelic variant, abolished PRG‐1 function by impeding its ability for LPA internalization due to altered glycosylation.Monoallelic PRG‐1 deficiency affected cortical information processing, leading to decreased somatosensory filter function in rodents and humans, and impaired resilience during stress‐related behaviors, an endophenotype of psychiatric disorders.Pharmacological intervention specifically targeting phospholipid signaling rescued cortical somatosensory filter function to wild‐type levels, opening a new therapeutic perspective for stress‐related mental dysfunctions. Graphical Abstract Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. bioactive phospholipids (dpeaa)DE-He213 cortical network (dpeaa)DE-He213 PRG‐1 (dpeaa)DE-He213 psychiatric disorders (dpeaa)DE-He213 synapse (dpeaa)DE-He213 Yang, Jenq‐Wei verfasserin aut Mobascher, Arian verfasserin aut Cheng, Jin verfasserin aut Li, Yunbo verfasserin aut Liu, Xingfeng verfasserin aut Baumgart, Jan verfasserin aut Thalman, Carine verfasserin aut Kirischuk, Sergei verfasserin aut Unichenko, Petr verfasserin aut Horta, Guilherme verfasserin aut Radyushkin, Konstantin verfasserin aut Stroh, Albrecht verfasserin aut Richers, Sebastian verfasserin aut Sahragard, Nassim verfasserin aut Distler, Ute verfasserin aut Tenzer, Stefan verfasserin aut Qiao, Lianyong verfasserin aut Lieb, Klaus verfasserin aut Tüscher, Oliver verfasserin aut Binder, Harald verfasserin aut Ferreiros, Nerea verfasserin aut Tegeder, Irmgard verfasserin aut Morris, Andrew J verfasserin aut Gropa, Sergiu verfasserin aut Nürnberg, Peter verfasserin aut Toliat, Mohammad R verfasserin aut Winterer, Georg verfasserin aut Luhmann, Heiko J verfasserin aut Huai, Jisen verfasserin aut Nitsch, Robert verfasserin aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 8(2015), 1 vom: 15. Dez., Seite 25-38 (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:8 year:2015 number:1 day:15 month:12 pages:25-38 https://dx.doi.org/10.15252/emmm.201505677 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_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_4367 GBV_ILN_4393 GBV_ILN_4700 AR 8 2015 1 15 12 25-38 |
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10.15252/emmm.201505677 doi (DE-627)SPR05790751X (SPR)emmm.201505677-e DE-627 ger DE-627 rakwb eng Vogt, Johannes verfasserin aut Molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene SNP 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors. Published under the terms of the CC BY 4.0 license 2015 Abstract Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐$ 1^{+/−} $ mice, which are animal correlates of human PRG‐$ 1^{+/mut} $ carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases. Synopsis Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. The human PRG‐1 SNP (R345T), present in a monoallelic variant, abolished PRG‐1 function by impeding its ability for LPA internalization due to altered glycosylation.Monoallelic PRG‐1 deficiency affected cortical information processing, leading to decreased somatosensory filter function in rodents and humans, and impaired resilience during stress‐related behaviors, an endophenotype of psychiatric disorders.Pharmacological intervention specifically targeting phospholipid signaling rescued cortical somatosensory filter function to wild‐type levels, opening a new therapeutic perspective for stress‐related mental dysfunctions. Graphical Abstract Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. bioactive phospholipids (dpeaa)DE-He213 cortical network (dpeaa)DE-He213 PRG‐1 (dpeaa)DE-He213 psychiatric disorders (dpeaa)DE-He213 synapse (dpeaa)DE-He213 Yang, Jenq‐Wei verfasserin aut Mobascher, Arian verfasserin aut Cheng, Jin verfasserin aut Li, Yunbo verfasserin aut Liu, Xingfeng verfasserin aut Baumgart, Jan verfasserin aut Thalman, Carine verfasserin aut Kirischuk, Sergei verfasserin aut Unichenko, Petr verfasserin aut Horta, Guilherme verfasserin aut Radyushkin, Konstantin verfasserin aut Stroh, Albrecht verfasserin aut Richers, Sebastian verfasserin aut Sahragard, Nassim verfasserin aut Distler, Ute verfasserin aut Tenzer, Stefan verfasserin aut Qiao, Lianyong verfasserin aut Lieb, Klaus verfasserin aut Tüscher, Oliver verfasserin aut Binder, Harald verfasserin aut Ferreiros, Nerea verfasserin aut Tegeder, Irmgard verfasserin aut Morris, Andrew J verfasserin aut Gropa, Sergiu verfasserin aut Nürnberg, Peter verfasserin aut Toliat, Mohammad R verfasserin aut Winterer, Georg verfasserin aut Luhmann, Heiko J verfasserin aut Huai, Jisen verfasserin aut Nitsch, Robert verfasserin aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 8(2015), 1 vom: 15. Dez., Seite 25-38 (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:8 year:2015 number:1 day:15 month:12 pages:25-38 https://dx.doi.org/10.15252/emmm.201505677 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_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_4367 GBV_ILN_4393 GBV_ILN_4700 AR 8 2015 1 15 12 25-38 |
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Enthalten in EMBO Molecular Medicine 8(2015), 1 vom: 15. Dez., Seite 25-38 volume:8 year:2015 number:1 day:15 month:12 pages:25-38 |
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EMBO Molecular Medicine |
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Vogt, Johannes @@aut@@ Yang, Jenq‐Wei @@aut@@ Mobascher, Arian @@aut@@ Cheng, Jin @@aut@@ Li, Yunbo @@aut@@ Liu, Xingfeng @@aut@@ Baumgart, Jan @@aut@@ Thalman, Carine @@aut@@ Kirischuk, Sergei @@aut@@ Unichenko, Petr @@aut@@ Horta, Guilherme @@aut@@ Radyushkin, Konstantin @@aut@@ Stroh, Albrecht @@aut@@ Richers, Sebastian @@aut@@ Sahragard, Nassim @@aut@@ Distler, Ute @@aut@@ Tenzer, Stefan @@aut@@ Qiao, Lianyong @@aut@@ Lieb, Klaus @@aut@@ Tüscher, Oliver @@aut@@ Binder, Harald @@aut@@ Ferreiros, Nerea @@aut@@ Tegeder, Irmgard @@aut@@ Morris, Andrew J @@aut@@ Gropa, Sergiu @@aut@@ Nürnberg, Peter @@aut@@ Toliat, Mohammad R @@aut@@ Winterer, Georg @@aut@@ Luhmann, Heiko J @@aut@@ Huai, Jisen @@aut@@ Nitsch, Robert @@aut@@ |
| publishDateDaySort_date |
2015-12-15T00:00:00Z |
| hierarchy_top_id |
594772761 |
| id |
SPR05790751X |
| language_de |
englisch |
| fullrecord |
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Published under the terms of the CC BY 4.0 license 2015</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐$ 1^{+/−} $ mice, which are animal correlates of human PRG‐$ 1^{+/mut} $ carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. The human PRG‐1 SNP (R345T), present in a monoallelic variant, abolished PRG‐1 function by impeding its ability for LPA internalization due to altered glycosylation.Monoallelic PRG‐1 deficiency affected cortical information processing, leading to decreased somatosensory filter function in rodents and humans, and impaired resilience during stress‐related behaviors, an endophenotype of psychiatric disorders.Pharmacological intervention specifically targeting phospholipid signaling rescued cortical somatosensory filter function to wild‐type levels, opening a new therapeutic perspective for stress‐related mental dysfunctions.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. 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Molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene SNP bioactive phospholipids (dpeaa)DE-He213 cortical network (dpeaa)DE-He213 PRG‐1 (dpeaa)DE-He213 psychiatric disorders (dpeaa)DE-He213 synapse (dpeaa)DE-He213 |
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Vogt, Johannes Yang, Jenq‐Wei Mobascher, Arian Cheng, Jin Li, Yunbo Liu, Xingfeng Baumgart, Jan Thalman, Carine Kirischuk, Sergei Unichenko, Petr Horta, Guilherme Radyushkin, Konstantin Stroh, Albrecht Richers, Sebastian Sahragard, Nassim Distler, Ute Tenzer, Stefan Qiao, Lianyong Lieb, Klaus Tüscher, Oliver Binder, Harald Ferreiros, Nerea Tegeder, Irmgard Morris, Andrew J Gropa, Sergiu Nürnberg, Peter Toliat, Mohammad R Winterer, Georg Luhmann, Heiko J Huai, Jisen Nitsch, Robert |
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molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene snp |
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Molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene SNP |
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Abstract Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐$ 1^{+/−} $ mice, which are animal correlates of human PRG‐$ 1^{+/mut} $ carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases. Synopsis Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. The human PRG‐1 SNP (R345T), present in a monoallelic variant, abolished PRG‐1 function by impeding its ability for LPA internalization due to altered glycosylation.Monoallelic PRG‐1 deficiency affected cortical information processing, leading to decreased somatosensory filter function in rodents and humans, and impaired resilience during stress‐related behaviors, an endophenotype of psychiatric disorders.Pharmacological intervention specifically targeting phospholipid signaling rescued cortical somatosensory filter function to wild‐type levels, opening a new therapeutic perspective for stress‐related mental dysfunctions. Graphical Abstract Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. © The Authors. Published under the terms of the CC BY 4.0 license 2015 |
| abstractGer |
Abstract Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐$ 1^{+/−} $ mice, which are animal correlates of human PRG‐$ 1^{+/mut} $ carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases. Synopsis Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. The human PRG‐1 SNP (R345T), present in a monoallelic variant, abolished PRG‐1 function by impeding its ability for LPA internalization due to altered glycosylation.Monoallelic PRG‐1 deficiency affected cortical information processing, leading to decreased somatosensory filter function in rodents and humans, and impaired resilience during stress‐related behaviors, an endophenotype of psychiatric disorders.Pharmacological intervention specifically targeting phospholipid signaling rescued cortical somatosensory filter function to wild‐type levels, opening a new therapeutic perspective for stress‐related mental dysfunctions. Graphical Abstract Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. © The Authors. Published under the terms of the CC BY 4.0 license 2015 |
| abstract_unstemmed |
Abstract Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐$ 1^{+/−} $ mice, which are animal correlates of human PRG‐$ 1^{+/mut} $ carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases. Synopsis Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. The human PRG‐1 SNP (R345T), present in a monoallelic variant, abolished PRG‐1 function by impeding its ability for LPA internalization due to altered glycosylation.Monoallelic PRG‐1 deficiency affected cortical information processing, leading to decreased somatosensory filter function in rodents and humans, and impaired resilience during stress‐related behaviors, an endophenotype of psychiatric disorders.Pharmacological intervention specifically targeting phospholipid signaling rescued cortical somatosensory filter function to wild‐type levels, opening a new therapeutic perspective for stress‐related mental dysfunctions. Graphical Abstract Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. © The Authors. Published under the terms of the CC BY 4.0 license 2015 |
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