Loss of prion protein control of glucose metabolism promotes neurodegeneration in model of prion diseases.
Corruption of cellular prion protein (PrPC) function(s) at the plasma membrane of neurons is at the root of prion diseases, such as Creutzfeldt-Jakob disease and its variant in humans, and Bovine Spongiform Encephalopathies, better known as mad cow disease, in cattle. The roles exerted by PrPC, howe...
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2021
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oai:doaj.org-article:e0f84de0ab084344b839c7190a6a90102021-12-02T20:00:04ZLoss of prion protein control of glucose metabolism promotes neurodegeneration in model of prion diseases.1553-73661553-737410.1371/journal.ppat.1009991https://doaj.org/article/e0f84de0ab084344b839c7190a6a90102021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009991https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Corruption of cellular prion protein (PrPC) function(s) at the plasma membrane of neurons is at the root of prion diseases, such as Creutzfeldt-Jakob disease and its variant in humans, and Bovine Spongiform Encephalopathies, better known as mad cow disease, in cattle. The roles exerted by PrPC, however, remain poorly elucidated. With the perspective to grasp the molecular pathways of neurodegeneration occurring in prion diseases, and to identify therapeutic targets, achieving a better understanding of PrPC roles is a priority. Based on global approaches that compare the proteome and metabolome of the PrPC expressing 1C11 neuronal stem cell line to those of PrPnull-1C11 cells stably repressed for PrPC expression, we here unravel that PrPC contributes to the regulation of the energetic metabolism by orienting cells towards mitochondrial oxidative degradation of glucose. Through its coupling to cAMP/protein kinase A signaling, PrPC tones down the expression of the pyruvate dehydrogenase kinase 4 (PDK4). Such an event favors the transfer of pyruvate into mitochondria and its conversion into acetyl-CoA by the pyruvate dehydrogenase complex and, thereby, limits fatty acids β-oxidation and subsequent onset of oxidative stress conditions. The corruption of PrPC metabolic role by pathogenic prions PrPSc causes in the mouse hippocampus an imbalance between glucose oxidative degradation and fatty acids β-oxidation in a PDK4-dependent manner. The inhibition of PDK4 extends the survival of prion-infected mice, supporting that PrPSc-induced deregulation of PDK4 activity and subsequent metabolic derangements contribute to prion diseases. Our study posits PDK4 as a potential therapeutic target to fight against prion diseases.Hélène ArnouldVincent BaudouinAnne BaudryLuiz W RibeiroHector Ardila-OsorioMathéa PietriCédric CaradeucCynthia SoultawiDeclan WilliamsMarjorie AlvarezCarole CrozetFatima DjouadiMireille LaforgeGildas BerthoOdile KellermannJean-Marie LaunayGerold Schmitt-UlmsBenoit SchneiderPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 10, p e1009991 (2021) |
| institution |
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| collection |
DOAJ |
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Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Hélène Arnould Vincent Baudouin Anne Baudry Luiz W Ribeiro Hector Ardila-Osorio Mathéa Pietri Cédric Caradeuc Cynthia Soultawi Declan Williams Marjorie Alvarez Carole Crozet Fatima Djouadi Mireille Laforge Gildas Bertho Odile Kellermann Jean-Marie Launay Gerold Schmitt-Ulms Benoit Schneider Loss of prion protein control of glucose metabolism promotes neurodegeneration in model of prion diseases. |
| description |
Corruption of cellular prion protein (PrPC) function(s) at the plasma membrane of neurons is at the root of prion diseases, such as Creutzfeldt-Jakob disease and its variant in humans, and Bovine Spongiform Encephalopathies, better known as mad cow disease, in cattle. The roles exerted by PrPC, however, remain poorly elucidated. With the perspective to grasp the molecular pathways of neurodegeneration occurring in prion diseases, and to identify therapeutic targets, achieving a better understanding of PrPC roles is a priority. Based on global approaches that compare the proteome and metabolome of the PrPC expressing 1C11 neuronal stem cell line to those of PrPnull-1C11 cells stably repressed for PrPC expression, we here unravel that PrPC contributes to the regulation of the energetic metabolism by orienting cells towards mitochondrial oxidative degradation of glucose. Through its coupling to cAMP/protein kinase A signaling, PrPC tones down the expression of the pyruvate dehydrogenase kinase 4 (PDK4). Such an event favors the transfer of pyruvate into mitochondria and its conversion into acetyl-CoA by the pyruvate dehydrogenase complex and, thereby, limits fatty acids β-oxidation and subsequent onset of oxidative stress conditions. The corruption of PrPC metabolic role by pathogenic prions PrPSc causes in the mouse hippocampus an imbalance between glucose oxidative degradation and fatty acids β-oxidation in a PDK4-dependent manner. The inhibition of PDK4 extends the survival of prion-infected mice, supporting that PrPSc-induced deregulation of PDK4 activity and subsequent metabolic derangements contribute to prion diseases. Our study posits PDK4 as a potential therapeutic target to fight against prion diseases. |
| format |
article |
| author |
Hélène Arnould Vincent Baudouin Anne Baudry Luiz W Ribeiro Hector Ardila-Osorio Mathéa Pietri Cédric Caradeuc Cynthia Soultawi Declan Williams Marjorie Alvarez Carole Crozet Fatima Djouadi Mireille Laforge Gildas Bertho Odile Kellermann Jean-Marie Launay Gerold Schmitt-Ulms Benoit Schneider |
| author_facet |
Hélène Arnould Vincent Baudouin Anne Baudry Luiz W Ribeiro Hector Ardila-Osorio Mathéa Pietri Cédric Caradeuc Cynthia Soultawi Declan Williams Marjorie Alvarez Carole Crozet Fatima Djouadi Mireille Laforge Gildas Bertho Odile Kellermann Jean-Marie Launay Gerold Schmitt-Ulms Benoit Schneider |
| author_sort |
Hélène Arnould |
| title |
Loss of prion protein control of glucose metabolism promotes neurodegeneration in model of prion diseases. |
| title_short |
Loss of prion protein control of glucose metabolism promotes neurodegeneration in model of prion diseases. |
| title_full |
Loss of prion protein control of glucose metabolism promotes neurodegeneration in model of prion diseases. |
| title_fullStr |
Loss of prion protein control of glucose metabolism promotes neurodegeneration in model of prion diseases. |
| title_full_unstemmed |
Loss of prion protein control of glucose metabolism promotes neurodegeneration in model of prion diseases. |
| title_sort |
loss of prion protein control of glucose metabolism promotes neurodegeneration in model of prion diseases. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/e0f84de0ab084344b839c7190a6a9010 |
| work_keys_str_mv |
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| _version_ |
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