From Scavenger to Metabolic Coordinator: Novel Roles of LRP1 in the CNS Myelin Development and Repair

[摘要] Low-density lipoprotein receptor-related protein-1 (LRP1) is one of the most versatile receptors. LRP1 is ubiquitously expressed and best known for its role as a scavenger receptor. The LRP1 extracellular domain binds to and participates in internalization of over 40 different ligands, and thereby regulates myriad cellular functions by recycling components of key pathways. The intracellular domain of LRP1 can undergo phosphorylation at specific tyrosine residues and thereby influence intracellular signaling pathways. In addition, the intracellular domain of LRP1 can be enzymatically processed, translocate to the nucleus, and function as a transcriptional co-regulator. In the developing nervous system, Lrp1 mRNA expression is highest in oligodendrocyte (OL) progenitor cells and rapidly decreases as OLs mature; however, whether LRP1 plays a role in OL development in vivo, remains elusive. Moreover, glial cells bind and internalize myelin breakdown products in an LRP1-dependent manner. As protracted clearance of myelin debris in the CNS is a hallmark of neuronal degeneration and demyelination diseases, the removal of myelin breakdown products through LRP1 might facilitate functional repair. Here we make use of global inducible and tissue-specific Lrp1 gene ablation in transgenic mice to assess the roles of LRP1 during CNS myelin development and repair. We found that myelin regeneration is attenuated in the absence of Lrp1; this defect is likely because of its role in OL maturation and myelin biogenesis. Mechanistic studies revealed that Lrp1 deficiency disrupts multiple pathways implicated in OL differentiation, including AKT activation, cholesterol homeostasis, PPARγ signaling, and peroxisome biogenesis. Moreover, the subcellular distribution of peroxisomes is altered and accompanied by a thinning of cytosolic spaces in OL processes. The impeded differentiation of cells in the OL lineage of Lrp1 null mice is largely rescued by bath application of free cholesterol and activation of PPARγ. This combo treatment improves peroxisome distribution into OL processes and formation of myelin sheets. Collectively, we have identified novel roles of LRP1 during CNS myelin development and white matter repair.

[发布机构] University of Michigan

[效力级别] CNS myelin repair

[关键词] CNS myelin development;CNS myelin repair;Oligodendrocyte;LRP1;Peroxisome biogenesis;Cholesterol homeostasis;Molecular;Cellular and Developmental Biology;Science;Cell and Developmental Biology