Peroxisome Injury in Multiple Sclerosis: Protective Effects of 4-Phenylbutyrate in CNS-Associated Macrophages

Andrej Roczkowsky, Matthew A.L. Doan, Brittyne A. Hlavay, Manmeet K. Mamik, William G. Branton, Brienne A. McKenzie, Leina B. Saito, Laura Schmitt, Gary Eitzen, Francesca Di Cara, Melinda Wuest, Frank Wuest, Richard Rachubinski, Christopher Power

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

Multiple sclerosis (MS) is a progressive and inflammatory demyelinating disease of the CNS. Peroxisomes perform critical functions that contribute to CNS homeostasis. We investigated peroxisome injury and mitigating effects of peroxisome-restorative therapy on inflammatory demyelination in models of MS. Human autopsied CNS tissues (male and female), human cell cultures, and cuprizonemediated demyelination mice (female) were examined by RT-PCR, Western blotting, and immunolabeling. The therapeutic peroxisome proliferator, 4-phenylbutyrate (4-PBA) was investigated in vitro and in vivo. White matter from MS patients showed reduced peroxisomal transcript and protein levels, including PMP70, compared with non-MS controls. Cultured human neural cells revealed that human microglia contained abundant peroxisomal proteins. TNF-α-exposed microglia displayed reduced immunolabeling of peroxisomal proteins, PMP70 and PEX11β, which was prevented with 4-PBA. In human myeloid cells exposed to TNF-α or nigericin, suppression of PEX11β and catalase protein levels were observed to be dependent on NLRP3 expression. Hindbrains from cuprizoneexposed mice showed reduced Abcd1, Cat, and Pex5l transcript levels, with concurrent increased Nlrp3 and Il1b transcript levels, which was abrogated by 4-PBA. In the central corpus callosum, Iba-1 in CNS-associated macrophages and peroxisomal thiolase immunostaining after cuprizone exposure was increased by 4-PBA. 4-PBA prevented decreased myelin basic protein and neurofilament heavy chain immunoreactivity caused by cuprizone exposure. Cuprizone-induced neurobehavioral deficits were improved by 4-PBA treatment. Peroxisome injury in CNS-associated macrophages contributed to neuroinflammation and demyelination that was prevented by 4-PBA treatment. A peroxisome-targeted therapy might be valuable for treating inflammatory demyelination and neurodegeneration in MS.

Original languageEnglish
Pages (from-to)7152-7165
Number of pages14
JournalJournal of Neuroscience
Volume42
Issue number37
DOIs
Publication statusPublished - Sept 14 2022

Bibliographical note

Funding Information:
This work was supported by MS Society of Canada to C.P. L.B.S. was supported by endMS Personnel Award from Multiple Sclerosis Society of Canada. B.A.M. and M.K.M. were supported by Alberta Innovates Health Solutions. B.A.M. was supported by the Canadian Institutes of Health Research. We thank Dr. Dan Muruve for provision of the THP-1 cell lines. The authors declare no competing financial interests. Correspondence should be addressed to Christopher Power at chris.power@ualberta.ca. https://doi.org/10.1523/JNEUROSCI.0312-22.2022 Copyright © 2022 the authors

Publisher Copyright:
© 2022 the authors.

ASJC Scopus Subject Areas

  • General Medicine

PubMed: MeSH publication types

  • Journal Article

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