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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., Author summary Transmissible Spongiform Encephalopathies (TSEs), commonly named prion diseases, are caused by pathogenic prions PrPSc that trigger degeneration of neurons in the brain. Although 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. There is still to date no medicine to fight against TSEs. The current study demonstrates that the deregulation of PrPC regulatory function towards glucose metabolism contributes to neurodegeneration in prion diseases. In the brain of prion-infected mice, PrPSc-induced overactivation of pyruvate dehydrogenase kinase 4 (PDK4) and downstream reduction in mitochondria pyruvate dehydrogenase (PDH) activity promote a metabolic shift from glucose oxidative degradation to pro-oxidant fatty acids β-oxidation contributing to prion pathogenesis. The pharmacological inhibition of PDK4 extends the lifespan of prion-infected mice by rescuing normal glucose metabolism. This study opens up new avenues to design PDK4-based therapeutic strategies to combat TSEs.

International audience; The CMS4 mesenchymal subtype of colorectal cancer (CRC) is associated with poor prognosis and resistance to treatment. The cellular prion protein PrP C is overexpressed in CMS4 tumors and controls the expression of a panel of CMS4-specific genes in CRC cell lines. Here, we sought to investigate PrP C downstream pathways that may underlie its role in CMS4 CRC. By combining gene set enrichment analyses and gain and loss of function approaches in CRC cell lines, we identify the integrin-linked kinase ILK as a proximal effector of PrP C that mediates its control on the CMS4 phenotype. We further leveraged three independent large CRC cohorts to assess correlations in gene expression pattern with patient outcomes and found that ILK is overexpressed in CMS4 mesenchymal tumors and confers a poor prognosis, especially when combined with high expression of the PrP C encoding gene PRNP. Of note, we discovered that the PrP C-ILK signaling axis controls the expression and activity of the tryptophan metabolizing enzyme indoleamine 2,3 dioxygenase IDO1, a key player in immune tolerance. In addition, we monitored alterations in the levels of tryptophan and its metabolites of the kynurenine pathway in the plasma of metastatic CRC patients (n = 325) and we highlight their prognostic value in combination with plasma PrP C levels. Thus, the PrP C-ILK-IDO1 axis plays a key role in the mesenchymal subtype of CRC. PrP C and IDO1-targeted strategies may represent new avenues for patient stratification and treatment in CRC.

International audience; Mitochondrial fatty acid oxidation (FAO) and respiratory chain (RC) defects form a large group of inherited monogenic disorders sharing many common clinical and pathophysiological features, including disruption of mitochondrial bioenergetics, but also, for example, oxidative stress and accumulation of noxious metabolites. Interestingly, several transcription factors or co-activators exert transcriptional control on both FAO and RC genes, and can be activated by small molecules, opening to possibly common therapeutic approaches for FAO and RC deficiencies. Here, we review recent data on the potential of various drugs or small molecules targeting pivotal metabolic regulators: peroxisome proliferator activated receptors (PPARs), sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and protein kinase A (PKA)) or interacting with reactive oxygen species (ROS) signaling, to alleviate or to correct inborn FAO or RC deficiencies in cellular or animal models. The possible molecular mechanisms involved, in particular the contribution of mitochondrial biogenesis, are discussed. Applications of these pharmacological approaches as a function of genotype/phenotype are also addressed, which clearly orient toward personalized therapy. Finally, we propose that beyond the identification of individual candidate drugs/molecules, future pharmacological approaches should consider their combination, which could produce additive or synergistic effects that may further enhance their therapeutic potential. The inborn defects of mitochondrial fatty acid β-oxidation (FAO) and respiratory chain (RC) rank among the most frequent genetic disorders of energy metabolism in human [1]. Although both groups of diseases are often presented and discussed separately by clinicians and researchers, they share many common features. Among them: (i) both groups of disorders are caused by the partial or total loss of function of a single protein or enzyme essential to the mitochondrial RC or to the FAO pathway; (ii) a large number of disease-causing genes have been identified, and each individual disorder is generally associated with a wide panel of gene mutations, with poorly understood genotype-phenotype correlations; (iii) the pathogenesis of these diseases involves not only bioenergetics defects due to disruption of mitochondrial structure and function, but also multiple other mechanisms-including ROS overproduction, oxidative stress, and accumulation of noxious intermediates; (iv) these disorders are clinically heterogeneous and can manifest in neonates, children, or adults with very diverse symptoms affecting one or several organs with high energy demand-including heart, skeletal muscle, liver, and brain; and (v) most of these disorders remain without treatment to date. Most importantly, and as we will see in this review, the FAO pathway and mitochondrial RC can be regulated, directly or indirectly, by the same transcription factors or co-activators, which leads to eventually propose the

International audience