LRP1 Regulates Peroxisome Biogenesis and Cholesterol Homeostasis in Oligodendrocytes and is Required in CNS Myelin Development and Repair

The low-density lipoprotein related-receptor-1 (LRP1) is a large endocytic and signaling receptor. We show that Lrp1 is required for proper CNS myelinogensis in vivo. Either global inducible or oligodendrocyte (OL)-lineage specific ablation of Lrp1 impairs myelin development and adult white matter repair. In primary oligodendrocyte progenitor cells (OPCs), Lrp1 deficiency reduces cholesterol levels and attenuates differentiation into mature OLs. Despite a strong increase in the sterol-regulatory element-binding protein-2, Lrp1 -/- OPCs are not able to maintain normal cholesterol levels, suggesting more global metabolic deficits. Mechanistic studies identified a decrease in peroxisomal biogenesis factor-2 and a reduction in peroxisomes localized to OL processes. Treatment of Lrp1 -/- OPCs with cholesterol or pharmacological activation of peroxisome proliferator-activated receptor-γ with pioglitazone is not sufficient to promote differentiation; however when combined, cholesterol and pioglitazone treatment enhance OL production. Collectively, our studies identify a novel link between LRP1, peroxisomes, and OPC differentiation during white matter development and repair. Introduction