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ResearchIn-Press PreviewCell biologyInflammationNeuroscience Open Access | 10.1172/JCI179985

Peroxisomal integrity in demyelination-associated microglia enables cellular debris clearance and myelin renewal in mice

Joseph A. Barnes-Vélez,1 Xiaohong Zhang,1 Yaren L. Peña Señeriz,2 Kiersten A. Scott,3 Yinglu Guan,1 and Jian Hu1

1Department of Cancer Biology, MD Anderson Cancer Center, Houston, United States of America

2University of Puerto Rico at Cayey, Cayey, Puerto Rico

3University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, United States of America

Find articles by Barnes-Vélez, J. in: PubMed | Google Scholar

1Department of Cancer Biology, MD Anderson Cancer Center, Houston, United States of America

2University of Puerto Rico at Cayey, Cayey, Puerto Rico

3University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, United States of America

Find articles by Zhang, X. in: PubMed | Google Scholar

1Department of Cancer Biology, MD Anderson Cancer Center, Houston, United States of America

2University of Puerto Rico at Cayey, Cayey, Puerto Rico

3University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, United States of America

Find articles by Peña Señeriz, Y. in: PubMed | Google Scholar

1Department of Cancer Biology, MD Anderson Cancer Center, Houston, United States of America

2University of Puerto Rico at Cayey, Cayey, Puerto Rico

3University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, United States of America

Find articles by Scott, K. in: PubMed | Google Scholar

1Department of Cancer Biology, MD Anderson Cancer Center, Houston, United States of America

2University of Puerto Rico at Cayey, Cayey, Puerto Rico

3University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, United States of America

Find articles by Guan, Y. in: PubMed | Google Scholar

1Department of Cancer Biology, MD Anderson Cancer Center, Houston, United States of America

2University of Puerto Rico at Cayey, Cayey, Puerto Rico

3University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, United States of America

Find articles by Hu, J. in: PubMed | Google Scholar |

Published November 6, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI179985.
Copyright © 2025, Barnes-Vélez et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 6, 2025 - Version history
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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 knockout of peroxisome biogenesis factor 5 (PEX5) in microglia. Absent demyelination, PEX5 conditional knockout (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, which features were largely absent in controls. Aberrant lipid processing was accompanied by elevated 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 necessary for enabling a pro-remyelinating environment.

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graphical abstract
Supplemental material

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View Supplemental Table 1: Gene markers for major cell types detected in brain specimens collected from control and PEX5cKO mice at baseline and CPZ conditions.

View Supplemental Table 2: Gene markers for immune sub-clusters detected in brain specimens collected from control and PEX5cKO mice at baseline and CPZ conditions.

View Supplemental Table 3: Differentially expressed genes with adjusted p value <0.15 detected from pseudobulk analysis between PEX5cKO and control genotypes across immune sub-clusters within the CPZ condition.

View Supplemental Table 4: Result tables from differentially expressed gene analysis performed between DMAM2 and DMAM0 clusters and between DMAM2 and DMAM1 clusters.

View Supplemental Table 5: Differentially expressed genes (adjusted p value <0.01, absolute fold change >0.25, base mean expression >10) detected between PEX5cKO and control bone marrow-derived macrophages across resting, 24h, and 72h conditions.

View Supplemental Table 6: Marker genes of annotated microglia clusters from published single cell RNA sequencing datasets used to generate custom gene signatures for gene set enrichment analysis in bone marrow-derived macrophages.

View Supplemental Table 7: Gene markers for OPC and oligodendroglial lineage sub-clusters detected in brain specimens collected from control and PEX5cKO mice at baseline and CPZ conditions.

View Supplemental Table 8: Differentially expressed genes with adjusted p value <0.15 detected from pseudobulk analysis between PEX5cKO and control genotypes across oligodendroglia lineage sub-clusters within the CPZ condition.

Version history
  • Version 1 (November 6, 2025): In-Press Preview
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