Prostaglandin D2 Synthase Controls Schwann Cells Metabolism and Peripheral Myelin Homeostasis

We previously reported that in the absence of Prostaglandin D2 synthase (L‐PGDS) peripheral nerves are hypomyelinated in development while in adulthood they present aberrant myelin sheaths. We now demonstrate that L‐PGDS expressed in Schwann cells is part of a coordinated program that controls myelin homeostasis, describing a new physiological pathway implicated in preserving peripheral myelin. In vivo and in vitro lipidomic, metabolomic, and transcriptomic analyses confirmed that myelin lipids composition, Schwann cells' energetic metabolism, and key enzymes controlling these processes are altered in the absence of L‐PGDS. Moreover, Schwann cells undergo a metabolic rewiring, turn to acetate as the main energetic source, and produce ketone bodies to ensure glial cell and neuronal survival. All these changes correlate with morphological myelin alterations. Collectively, we posit that myelin lipids serve as a reservoir to provide ketone bodies, which together with acetate represent the adaptive substrates Schwann cells can rely on to sustain the axo‐glial unit and preserve the integrity of the PNS.