Scheme representation of metabolic abnormalities in the absence of PrP^C.

In PrP^null-cells, loss of PrP^C coupling to the cAMP/PKA signaling pathway abrogates PrP^C negative control of PPARγ and PDK4 expression. The subsequent rise in PDK4 level and activity leads to a reduction of PDH complex activity associated with a rise of phosphorylation of the PDHA1 subunit. This provokes a decrease of the glycolytic flux in favor of an increase in the fatty acids β-oxidation rate, which combined to the excess of synthesized ATP sustain high PDK4 activity. The in fuel preference of PrP^null-cells towards the use of fatty acids is accompanied by the onset of oxidative stress conditions. In PrP^C-expressing cells, PrP^C coupling to cAMP/PKA signaling tones down PPARγ/PDK4 expressions, which equilibrates carbohydrate and fatty acid degradations, and thereby confers anti-oxidative stress function to PrP^C.

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