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

Abstract

13The low--density lipoprotein related--receptor--1 (LRP1) is a large endocytic and signaling 14 receptor. We show that Lrp1 is required for proper CNS myelinogensis in vivo. Either global 15 inducible or oligodendrocyte (OL)--lineage specific ablation of Lrp1 impairs myelin 16 development and adult white matter repair. In primary oligodendrocyte progenitor cells 17 (OPCs), Lrp1 deficiency reduces cholesterol levels and attenuates differentiation into mature 18OLs. Despite a strong increase in the sterol--regulatory element--binding protein--2, Lrp1 --/--OPCs 19are not able to maintain normal cholesterol levels, suggesting more global metabolic deficits. 20Mechanistic studies identified a decrease in peroxisomal biogenesis factor--2 and a reduction 21 in peroxisomes localized to OL processes. Treatment of Lrp1 --/--OPCs with cholesterol or 22 pharmacological activation of peroxisome proliferator--activated receptor--γ with pioglitazone 23is not sufficient to promote differentiation; however when combined, cholesterol and 24 pioglitazone treatment enhance OL production. Collectively, our studies identify a novel link 25 between LRP1, peroxisomes, and OPC differentiation during white matter development and 26 repair. 27 not peer-reviewed)