# Dysregulated lipid metabolism and hypomyelination in postnatal peroxisome-deficient Pex2 knockout Zellweger mice

## TL;DR

This study shows that peroxisome deficiency in mice leads to disrupted cholesterol metabolism and reduced myelination in the brain, offering new insights into peroxisomal disorders.

## Contribution

The study reveals new insights into how peroxisome deficiency causes hypomyelination and dysregulated lipid metabolism in the CNS.

## Key findings

- Peroxisome-deficient mice show increased catalase activity and oxidative imbalance in the CNS.
- Cholesterol and sphingolipid metabolism are dysregulated in peroxisome-deficient mice.
- Reduced myelination is observed due to decreased mTORC1 activity and myelin marker levels.

## Abstract

Peroxisomes are dynamic organelles that play a crucial role in cellular metabolism, particularly in fatty acid degradation, cholesterol homeostasis and reactive oxygen species metabolism. Their dysfunction is associated with severe neurological disorders, including Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD). In this study, we investigated the relationship between cholesterol homeostasis and myelination in postnatal peroxisome-deficient Pex2 knockout mice. We dissected the central nervous system (CNS) of 10-day-old (P10) control and Pex2−/− mice into five regions: spinal cord, brainstem, cerebellum, diencephalon and cerebral cortex. Catalase activity, a marker enzyme of peroxisomes, was significantly increased in CNS regions of Pex2−/− mice, indicating an oxidative imbalance. Proteomic analysis revealed significant alterations in peroxisomal proteins and pathways related to neurodegenerative diseases, cholesterol and fatty acid metabolism and mRNA processing. Cholesterol biosynthesis was particularly dysregulated: enzyme activities, mRNA, and protein levels were reduced in white matter regions but increased in the cerebral cortex. The elevated desmosterol levels in the brain of Pex2−/− mice indicate impaired cholesterol synthesis. Sphingolipid metabolism was also altered in the peroxisome-deficient CNS, as the protein levels of enzymes dihydroceramide desaturase 1, ceramide synthase 2, fatty acid 2-hydroxylase, and UDP-glycosyltransferase 8 were significantly decreased. Myelination was significantly reduced throughout the CNS, as evidenced by decreased activities of the myelin marker 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP) and decreased mRNA and protein levels of myelin-associated proteins. The consistent decrease in ribosomal protein S6 phosphorylation in the CNS of Pex2−/− mice suggests that decreased mechanistic target of rapamycin complex 1 (mTORC1) activity contributes to hypomyelination. Gene expression analysis revealed an upregulation of pro-inflammatory cytokines and altered expression of some homeostatic and disease-associated microglial (DAM) genes. However, full DAM activation was not yet observed in Pex2−/− mice at P10. In conclusion, this study shows that systemic peroxisome deficiency leads to severe hypomyelination and dysregulation of cholesterol and fatty acid metabolism in the CNS, providing new insights into the pathophysiology of peroxisomal disorders.