LRP1 regulates peroxisome biogenesis and cholesterol homeostasis in oligodendrocytes and is required for proper CNS myelin development and repair

Low-density lipoprotein-related receptor-1 (LRP1) is a critical player in lipid metabolism, often found disrupted in various brain disorders. While the role of LRP1 in neurons is known, its significance in oligodendrocytes, the primary myelin lipid-producing cells in the central nervous system, is unclear. To address this gap, I pursued a Ph.D. at the University of Michigan Medical School, creating transgenic mouse lines to investigate the role of LRP1 in myelin formation and repair. LRP1 absence led to altered oligodendrocyte lipid metabolism, abnormal myelin structure, and impaired optic nerve conduction during development. Moreover, I developed a quantitative assay for unbiased myelin repair assessment in vivo, showing that LRP1 removal impedes recovery. To gain deeper mechanistic insights, I explored roles of LRP1 in myelinogenesis with an in vitro primary culture system. My findings indicated that altered cholesterol homeostasis and peroxisome biogenesis in LRP1-null oligodendrocytes could be restored by pharmacologically activating both pathways together rather than separately. My work uncovered the multifaceted role of LRP1 and suggested a combined treatment approach to enhance myelin formation.

Citation: Lin JP, Mironova YA, Shrager P, Giger RJ. eLife 2017 Dec
Download