{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:51:20Z","timestamp":1792792280146,"version":"4.5.0"},"reference-count":253,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["DK58040"],"award-info":[{"award-number":["DK58040"]}]},{"name":"NIH","award":["DK58238"],"award-info":[{"award-number":["DK58238"]}]},{"name":"National Institutes of Health\/National Institutes of General Medical Sciences","award":["R25GM58906"],"award-info":[{"award-number":["R25GM58906"]}]},{"name":"National Institutes of Health\/National Institutes of General Medical Sciences","award":["T34GM008303"],"award-info":[{"award-number":["T34GM008303"]}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["320030_236268"],"award-info":[{"award-number":["320030_236268"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["310030_192614"],"award-info":[{"award-number":["310030_192614"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["31003A_166245"],"award-info":[{"award-number":["31003A_166245"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>\n                    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\n                    <jats:italic>Pex2<\/jats:italic>\n                    knockout mice. We dissected the central nervous system (CNS) of 10-day-old (P10) control and\n                    <jats:italic>Pex2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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\n                    <jats:italic>Pex2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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\n                    <jats:italic>Pex2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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\u2032,3\u2032-cyclic nucleotide 3\u2032-phosphodiesterase (CNP) and decreased mRNA and protein levels of myelin-associated proteins. The consistent decrease in ribosomal protein S6 phosphorylation in the CNS of\n                    <jats:italic>Pex2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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\n                    <jats:italic>Pex2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.3389\/fnmol.2026.1636268","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T06:45:33Z","timestamp":1771915533000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Dysregulated lipid metabolism and hypomyelination in postnatal peroxisome-deficient Pex2 knockout Zellweger mice"],"prefix":"10.3389","volume":"19","author":[{"given":"Tanja","family":"Eberhart","sequence":"first","affiliation":[{"name":"Institute of Molecular Health Sciences, ETH Zurich","place":["Zurich, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khanichi N.","family":"Charles","sequence":"additional","affiliation":[{"name":"Department of Biology, San Diego State University","place":["San Diego, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Salumbides-Torres","sequence":"additional","affiliation":[{"name":"Department of Biology, San Diego State University","place":["San Diego, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nia","family":"Price","sequence":"additional","affiliation":[{"name":"Department of Biology, San Diego State University","place":["San Diego, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J.","family":"Fliesler","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Biochemistry and Graduate Program in Neuroscience, University at Buffalo-The State University of New York (SUNY)","place":["Buffalo, NY, United States"]},{"name":"Research Service, Veterans Administration Western New York Healthcare System","place":["Buffalo, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phyllis L.","family":"Faust","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner J.","family":"Kovacs","sequence":"additional","affiliation":[{"name":"Institute of Molecular Health Sciences, ETH Zurich","place":["Zurich, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1016\/0736-5748(86)90003-1","article-title":"A possible relationship between concentration of microperoxisomes and myelination","volume":"4","author":"Adamo","year":"1986","journal-title":"Int. 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