Abstract
Low-density lipoprotein receptor-related protein-1 (LRP1) is a large endocytic and signaling molecule broadly expressed by neurons and glia. In adult mice, global inducible (Lrp1flox/flox;CAG-CreER) or oligodendrocyte (OL)-lineage specific ablation (Lrp1flox/flox;Pdgfra-CreER) of Lrp1 attenuates repair of damaged white matter. In oligodendrocyte progenitor cells (OPCs), Lrp1 is required for cholesterol homeostasis and differentiation into mature OLs. Lrp1-deficient OPC/OLs show a strong increase in the sterol-regulatory element-binding protein-2 yet are unable to maintain normal cholesterol levels, suggesting more global metabolic deficits. Mechanistic studies revealed a decrease in peroxisomal biogenesis factor-2 and fewer peroxisomes in OL processes. Treatment of Lrp1-/- OPCs with cholesterol or activation of peroxisome proliferator-activated receptor-γ with pioglitazone alone is not sufficient to promote differentiation; however, when combined, cholesterol and pioglitazone enhance OPC differentiation into mature OLs. Collectively, our studies reveal a novel role for Lrp1 in peroxisome biogenesis, lipid homeostasis, and OPC differentiation during white matter development and repair.
Highlights
In the central nervous system (CNS), the myelin-‐producing cell is the oligodendrocyte (OL)
Lrp1 is required for proper CNS myelin development
To assay whether lipoprotein related-‐receptor-‐1 (LRP1) is required for proper CNS myelinogenesis, neonatal Lrp1 control and iKO mice were subjected to TM injection at P5 and analyzed at P21 (Figure 1a)
Summary
In the central nervous system (CNS), the myelin-‐producing cell is the oligodendrocyte (OL). Global deletion of Lrp is embryonically lethal (Herz et al, 1992) and conditional deletion revealed numerous tissue specific functions in neural and non-‐neural cell types (Lillis et al, 2008). In the CNS, Lrp influences neural stem cell proliferation (Auderset et al, 2016), synaptic strength (Nakajima et al, 2013, Gan et al, 2014), axonal regeneration (Stiles et al., 2013, Yoon et al, 2013, Landowski et al, 2016), and clearance of amyloid beta (Liu et al., 2010, Zlokovic et al, 2010, Kanekiyo and Bu, 2014, Kim et al, 2014). Recent evidence shows that neurospheres deficient for Lrp produce more GFAP+ astrocytes at the expense of O4+
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