Unbiased Screening Approaches Reveal Unique Sterol Biology and a Unifying Mechanism for Sterol-Driven Oligodendrocyte Formation

Myelin is a lipid-rich substance in the CNS responsible for supporting neuronal axon function. Myelin is critical for saltatory conduction, the quick ‘jumping’ of action potentials down the axons to facilitate efficient neuronal signaling. Oligodendrocytes are supportive cells resident in the CNS and are responsible for producing this myelin. The loss of myelin and the oligodendrocytes that produce it is the basis for neuronal diseases that affect millions. Demyelinating disease and the most common form, multiple sclerosis, results from autoimmune destruction of myelin leading to progressive disease with symptoms including blurry vision, balance and coordination issues, and in chronic, severe cases, leaving patients wheelchair bound for the rest of their lives. Demyelinating diseases, like multiple sclerosis, are typically treated with immunomodulatory therapies, which can have harmful side effects and do not alter long-term outcomes. Remyelination, however, may change the course of the disease. Oligodendrocyte precursor cells (OPCs) can differentiate into mature, myelinating oligodendrocytes, potentially replacing lost oligodendrocytes and myelin resulting from autoimmune damage. Developing drugs to promote OPC differentiation could improve prognosis and alter the course of the disease. Our work and the work of previous labs focus on understanding the mechanism of most remyelinating drugs. Namely, these drugs drive OPC differentiation by inhibiting enzymes of the cholesterol biosynthesis pathway, CYP51, sterol 14-reductase, EBP, LSS, HSD17B7, and SC4MOL. This in turn leads to the accumulation of sterol substrates for each of these enzymes which ultimately are sufficient to drive the differentiation phenotype. This work also shows the importance of oxysterol binding proteins, involved in maintaining cholesterol homeostasis, in sterol biology as the genetic and chemical inhibition of the protein led to strikingly potent cytotoxicity specific to OPCs and oligodendrocytes. Overall, this work furthers the significance of sterol-driven oligodendrocyte formation in remyelination and sets a mechanistic framework for future remyelinating drug development in the pursuit of a cure for demyelinating disease.