Hyperactivation of Hedgehog signaling impedes myelin development and repair via cholesterol dysregulation in oligodendrocytes

The failure to remyelinate demyelinated axons poses a significant challenge in the treatment of multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system. Here, we investigated the role of Hedgehog (Hh) signaling in myelin formation during development and under pathological conditions. Using conditional gain-of-function analyses, we found that hyperactivation of Hh signaling in oligodendrocyte precursor cells (OPCs) inhibits oligodendrocyte (OL) differentiation and myelination. Notably, sustained activation of Hh signaling in adult OPCs hinders myelin repair following LPC-induced focal demyelination. Through RNA sequencing, we discovered that genes associated with cholesterol synthesis were upregulated, and observed intracellular cholesterol accumulation in Hh-activated OPCs. Importantly, pharmacological stimulation of cholesterol transport was able to rescue the OL differentiation and myelination defects in mice. These findings establish a functional connection between Hh signaling, cholesterol homeostasis, and remyelination, providing insights for the strategic design of employing Hh signaling modulators in treating demyelinating neurodegenerative diseases.