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Updated: Aug 16, 2026
Two-photon Imaging of Cellular Dynamics in the Mouse Spinal Cord
Published on: February 22, 2015
Peroxisomal integrity in demyelination-associated microglia enables cellular debris clearance and myelin renewal in
Joseph A Barnes-Vélez1,2,3, Xiaohong Zhang1, Yaren L Peña Señeriz4
1Department of Cancer Biology, MD Anderson Cancer Center, Houston, Texas, USA.
Abstract:
Demyelination associated microglia (DMAM) orchestrate the regenerative response to demyelination by clearing myelin debris and promoting oligodendrocyte maturation. Peroxisomal metabolism has emerged as a candidate regulator of DMAMs, though the cell-intrinsic contribution in microglia remains undefined. Here we elucidate the role of peroxisome integrity in DMAMs, using cuprizone-mediated demyelination coupled with conditional KO of peroxisome biogenesis factor 5 (PEX5) in microglia. Absent demyelination, PEX5 conditional KO (PEX5cKO) had minimal impact on homeostatic microglia. However, during cuprizone-induced demyelination, the emergence of DMAMs unmasked a critical requirement for peroxisome integrity. At peak demyelination, PEX5cKO DMAMs exhibited increased lipid droplet burden and reduced lipophagy suggestive of impaired lipid catabolism. Although lipid droplet burden declined during the remyelination phase, PEX5cKO DMAMs accumulated intralysosomal crystals and curvilinear profiles, features that were largely absent in controls. Aberrant lipid processing was accompanied by elevated numbers of lysosomal damage markers and downregulation of the lipid exporter gene Apoe, consistent with defective lipid clearance. Furthermore, the disruptions in PEX5cKO DMAMs were associated with defective myelin debris clearance and impaired remyelination. Together, these findings delineate a stage-specific role for peroxisomes in coordinating lipid processing pathways essential to DMAM function and for enabling a pro-remyelinating environment.
Insights
Peroxisome integrity is crucial for microglia (DMAMs) to clear myelin debris and promote repair after demyelination. Disrupting peroxisome biogenesis in DMAMs impairs lipid processing, hindering myelin clearance and remyelination.
Area of Science:
- Neuroscience
- Cell Biology
- Metabolic pathways
Background:
- Demyelination-associated microglia (DMAMs) are key players in myelin repair.
- The role of peroxisomal metabolism within microglia during demyelination is not well understood.
Purpose of the Study:
- To investigate the cell-intrinsic role of peroxisome integrity in DMAM function during demyelination and remyelination.
- To determine if peroxisome biogenesis factor 5 (PEX5) is essential for DMAMs.
Main Methods:
- Utilized a cuprizone-induced demyelination model in mice.
- Generated microglia-specific conditional knockout (cKO) of PEX5 (PEX5cKO).
- Analyzed DMAM morphology, lipid metabolism, lysosomal function, and remyelination.
Main Results:
- PEX5cKO had minimal effects on homeostatic microglia but critically impaired DMAMs during demyelination.
- PEX5cKO DMAMs showed impaired lipid catabolism, increased lipid droplets, and reduced lipophagy.
- Defective DMAMs accumulated intralysosomal crystals and curvilinear profiles, indicating aberrant lipid processing and lysosomal damage.
- Impaired DMAMs exhibited reduced myelin debris clearance and defective remyelination.
Conclusions:
- Peroxisome integrity, regulated by PEX5, is essential for DMAMs to effectively process lipids during demyelination.
- Disruption of peroxisomal function in DMAMs leads to impaired myelin clearance and remyelination.
- This study highlights a stage-specific role for peroxisomes in supporting DMAMs and promoting central nervous system repair.
