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Loss of prion protein control of glucose metabolism promotes neurodegeneration in model of prion diseases.
Arnould, Hélène; Baudouin, Vincent; Baudry, Anne; Ribeiro, Luiz W; Ardila-Osorio, Hector; Pietri, Mathéa; Caradeuc, Cédric; Soultawi, Cynthia; Williams, Declan; Alvarez, Marjorie; Crozet, Carole; Djouadi, Fatima; Laforge, Mireille; Bertho, Gildas; Kellermann, Odile; Launay, Jean-Marie; Schmitt-Ulms, Gerold; Schneider, Benoit.
Afiliación
  • Arnould H; INSERM, UMR-S 1124, Paris, France.
  • Baudouin V; Université de Paris, UMR-S 1124, Paris, France.
  • Baudry A; INSERM, UMR-S 1124, Paris, France.
  • Ribeiro LW; Université de Paris, UMR-S 1124, Paris, France.
  • Ardila-Osorio H; INSERM, UMR-S 1124, Paris, France.
  • Pietri M; Université de Paris, UMR-S 1124, Paris, France.
  • Caradeuc C; INSERM, UMR-S 1124, Paris, France.
  • Soultawi C; Université de Paris, UMR-S 1124, Paris, France.
  • Williams D; INSERM, UMR-S 1124, Paris, France.
  • Alvarez M; Université de Paris, UMR-S 1124, Paris, France.
  • Crozet C; INSERM, UMR-S 1124, Paris, France.
  • Djouadi F; Université de Paris, UMR-S 1124, Paris, France.
  • Laforge M; CNRS, UMR 8601, Paris, France.
  • Bertho G; Université de Paris, UMR 8601, Paris, France.
  • Kellermann O; INSERM, UMR-S 1124, Paris, France.
  • Launay JM; Université de Paris, UMR-S 1124, Paris, France.
  • Schmitt-Ulms G; University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Canada.
  • Schneider B; INSERM, UMR-S 1124, Paris, France.
PLoS Pathog ; 17(10): e1009991, 2021 10.
Article en En | MEDLINE | ID: mdl-34610054
ABSTRACT
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 ß-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 ß-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.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Enfermedades por Prión / Proteínas PrPSc / Glucosa / Degeneración Nerviosa Límite: Animals Idioma: En Revista: PLoS Pathog Año: 2021 Tipo del documento: Article País de afiliación: Francia

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Enfermedades por Prión / Proteínas PrPSc / Glucosa / Degeneración Nerviosa Límite: Animals Idioma: En Revista: PLoS Pathog Año: 2021 Tipo del documento: Article País de afiliación: Francia