Compromised Myelin and Axonal Molecular Organization Following Adult-Onset Sulfatide Depletion

Elizabeth Dustin, Edna Suarez-Pozos, Camryn Stotesberry, Shulan Qiu, Juan Pablo Palavicini, Xianlin Han, Jeffrey L. Dupree

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

3-O-sulfogalactosylceramide, or sulfatide, is a prominent myelin glycosphingolipid reduced in the normal appearing white matter (NAWM) in Multiple Sclerosis (MS), indicating that sulfatide reduction precedes demyelination. Using a mouse model that is constitutively depleted of sulfatide, we previously demonstrated that sulfatide is essential during development for the establishment and maintenance of myelin and axonal integrity and for the stable tethering of certain myelin proteins in the sheath. Here, using an adult-onset depletion model of sulfatide, we employ a combination of ultrastructural, immunohistochemical and biochemical approaches to analyze the consequence of sulfatide depletion from the adult CNS. Our findings show a progressive loss of axonal protein domain organization, which is accompanied by axonal degeneration, with myelin sparing. Similar to our previous work, we also observe differential myelin protein anchoring stabilities that are both sulfatide dependent and independent. Most notably, stable anchoring of neurofascin155, a myelin paranodal protein that binds the axonal paranodal complex of contactin/Caspr1, requires sulfatide. Together, our findings show that adult-onset sulfatide depletion, independent of demyelination, is sufficient to trigger progressive axonal degeneration. Although the pathologic mechanism is unknown, we propose that sulfatide is required for maintaining myelin organization and subsequent myelin–axon interactions and disruptions in these interactions results in compromised axon structure and function.

Original languageEnglish (US)
Article number1431
JournalBiomedicines
Volume11
Issue number5
DOIs
StatePublished - May 2023

Keywords

  • lipid rafts
  • multiple sclerosis
  • myelin
  • sphingolipid
  • sulfatide

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • Medicine (miscellaneous)

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