LRP1 regulates peroxisome biogenesis and cholesterol homeostasis in oligodendrocytes and is required for proper CNS myelin development and repair
- University of Michigan, United States
- University of Rochester Medical Center, United States
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.
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Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007505)
- Yevgeniya A Mironova
National Institute of General Medical Sciences (T32GM007315)
- Yevgeniya A Mironova
National Institute of Neurological Disorders and Stroke (R01NS081281)
- Peter Shrager
National Institute of Neurological Disorders and Stroke (R01NS081281)
- Roman J Giger
Schmitt Program on Integrative Brain Research
- Peter Shrager
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (APNRR)
- Roman J Giger
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to protocols approved by the University committee on use and care for animals (IACUC protocols: #00005863 and #00005896) of the University of Michigan.
Copyright
© 2017, Lin et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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LRP1 regulates peroxisome biogenesis and cholesterol homeostasis in oligodendrocytes and is required for proper CNS myelin development and repair
eLife 6:e30498.
https://doi.org/10.7554/eLife.30498
