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

  1. Jing-Ping Lin
  2. Yevgeniya A Mironova
  3. Peter Shrager
  4. Roman J Giger  Is a corresponding author
  1. University of Michigan, United States
  2. 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.

Article and author information

Author details

  1. Jing-Ping Lin

    Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0686-0215
  2. Yevgeniya A Mironova

    Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Peter Shrager

    Department of Neuroscience, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Roman J Giger

    Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States
    For correspondence
    rgiger@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2926-3336

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.

Metrics

  • 4,647
    views
  • 745
    downloads
  • 43
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jing-Ping Lin
  2. Yevgeniya A Mironova
  3. Peter Shrager
  4. Roman J Giger
(2017)
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

Share this article

https://doi.org/10.7554/eLife.30498

Further reading

    1. Neuroscience
    Kayson Fakhar, Fatemeh Hadaeghi ... Claus C Hilgetag
    Research Article

    Efficient communication in brain networks is foundational for cognitive function and behavior. However, how communication efficiency is defined depends on the assumed model of signaling dynamics, e.g., shortest path signaling, random walker navigation, broadcasting, and diffusive processes. Thus, a general and model-agnostic framework for characterizing optimal neural communication is needed. We address this challenge by assigning communication efficiency through a virtual multi-site lesioning regime combined with game theory, applied to large-scale models of human brain dynamics. Our framework quantifies the exact influence each node exerts over every other, generating optimal influence maps given the underlying model of neural dynamics. These descriptions reveal how communication patterns unfold if regions are set to maximize their influence over one another. Comparing these maps with a variety of brain communication models showed that optimal communication closely resembles a broadcasting regime in which regions leverage multiple parallel channels for information dissemination. Moreover, we found that the brain’s most influential regions are its rich-club, exploiting their topological vantage point by broadcasting across numerous pathways that enhance their reach even if the underlying connections are weak. Altogether, our work provides a rigorous and versatile framework for characterizing optimal brain communication, and uncovers the most influential brain regions, and the topological features underlying their influence.

    1. Neuroscience
    Poortata Lalwani, Thad Polk, Douglas D Garrett
    Research Article

    Moment-to-moment neural variability has been shown to scale positively with the complexity of stimulus input. However, the mechanisms underlying the ability to align variability to input complexity are unknown. Using a combination of behavioral methods, computational modeling, fMRI, MR spectroscopy, and pharmacological intervention, we investigated the role of aging and GABA in neural variability during visual processing. We replicated previous findings that participants expressed higher variability when viewing more complex visual stimuli. Additionally, we found that such variability modulation was associated with higher baseline visual GABA levels and was reduced in older adults. When pharmacologically increasing GABA activity, we found that participants with lower baseline GABA levels showed a drug-related increase in variability modulation while participants with higher baseline GABA showed no change or even a reduction, consistent with an inverted-U account. Finally, higher baseline GABA and variability modulation were jointly associated with better visual-discrimination performance. These results suggest that GABA plays an important role in how humans utilize neural variability to adapt to the complexity of the visual world.