LRP1 regulates peroxisome biogenesis and cholesterol homeostasis in oligodendrocytes and is required for proper CNS myelin development and repair.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29251594.
- Also identified by DOI 10.7554/eLife.30498 and PMC identifier 5752207.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 (<i>Lrp1<sup>flox/flox</sup>;CAG-CreER</i>) or oligodendrocyte (OL)-lineage specific ablation (<i>Lrp1<sup>flox/flox</sup>;Pdgfra-CreER</i>) of <i>Lrp1</i> attenuates repair of damaged white matter. In oligodendrocyte progenitor cells (OPCs), <i>Lrp1</i> is required for cholesterol homeostasis and differentiation into mature OLs. <i>Lrp1-</i>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 <i>Lrp1<sup>-/-</sup></i> 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 <i>Lrp1</i> in peroxisome biogenesis, lipid homeostasis, and OPC differentiation during white matter development and repair.
Medical subject headings
- Cholesterol
- Homeostasis
- Myelin Sheath
- Oligodendrocyte Precursor Cells
- Organelle Biogenesis
- Peroxisomes
- Receptors, LDL
- Tumor Suppressor Proteins