Loss of prion protein control of glucose metabolism promotes neurodegeneration in model of prion diseases.

Hélène Arnould,Jean-Marie Launay,Anne Baudry,Hector Ardila-Osorio,Fatima Djouadi,Odile Kellermann,Vincent Baudouin,Benoit Schneider,Gerold Schmitt-Ulms,Carole Crozet,Mireille Laforge,Luiz W Ribeiro,Cédric Caradeuc,Declan Williams,Cynthia Soultawi,Mathéa Pietri,Marjorie Alvarez,Gildas Bertho

doi:10.1371/journal.ppat.1009991

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 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.

Highlights

The cellular prion protein PrPC is mainly known for its implication in Transmissible Spongiform Encephalopathies (TSEs), commonly named prion diseases [1], and has been more recently involved in two other unrelated amyloid-based neurodegenerative pathologies, the Alzheimer’s [2,3] and Parkinson’s [4,5] diseases
PrPSc exerts its neurotoxicity by corrupting the function(s) of normal cellular prion protein (PrPC), our understanding of the mechanisms involved in prion diseases remains limited
The current study demonstrates that the deregulation of PrPC regulatory function towards glucose metabolism contributes to neurodegeneration in prion diseases

Summary

Introduction

The cellular prion protein PrPC is mainly known for its implication in Transmissible Spongiform Encephalopathies (TSEs), commonly named prion diseases [1], and has been more recently involved in two other unrelated amyloid-based neurodegenerative pathologies, the Alzheimer’s [2,3] and Parkinson’s [4,5] diseases. Identifying the role(s) exerted by PrPC in neurons is a prerequisite to grasp the nature and sequence of events occurring in those neurodegenerative disorders, for which several neuronal abnormalities have already been reported, including oxidative stress [10], endoplasmic reticulum stress [11], autophagy deficits [12,13], mitochondria dysfunctions [10,14] and/or energetic metabolic dysregulation [15,16,17,18,19,20]. The absence of a clear phenotype for PrPnull mice suggested mechanisms occurring early during embryogenesis that would compensate for the lack of PrPC [26], making it difficult to unravel PrPC function(s) with PrPnull mice

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