Compromised Myelin and Axonal Molecular Organization Following Adult-Onset Sulfatide Depletion
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 previous...
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MDPI AG
2023-05-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/5/1431 |
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| author | Elizabeth Dustin Edna Suarez-Pozos Camryn Stotesberry Shulan Qiu Juan Pablo Palavicini Xianlin Han Jeffrey L. Dupree |
| author_facet | Elizabeth Dustin Edna Suarez-Pozos Camryn Stotesberry Shulan Qiu Juan Pablo Palavicini Xianlin Han Jeffrey L. Dupree |
| author_sort | Elizabeth Dustin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T03:54:27Z |
| format | Article |
| id | doaj.art-1d2f112626b94201876886b0f33dc555 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T03:54:27Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-1d2f112626b94201876886b0f33dc5552023-11-18T00:36:59ZengMDPI AGBiomedicines2227-90592023-05-01115143110.3390/biomedicines11051431Compromised Myelin and Axonal Molecular Organization Following Adult-Onset Sulfatide DepletionElizabeth Dustin0Edna Suarez-Pozos1Camryn Stotesberry2Shulan Qiu3Juan Pablo Palavicini4Xianlin Han5Jeffrey L. Dupree6Research Service, Richmond Veterans Affairs Medical Center, Central Virginia Veterans Affairs Health Care System, Richmond, VA 23249, USAResearch Service, Richmond Veterans Affairs Medical Center, Central Virginia Veterans Affairs Health Care System, Richmond, VA 23249, USADepartment of Biology, Virginia Commonwealth University, Richmond, VA 23298, USASam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USASam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USASam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USAResearch Service, Richmond Veterans Affairs Medical Center, Central Virginia Veterans Affairs Health Care System, Richmond, VA 23249, USA3-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.https://www.mdpi.com/2227-9059/11/5/1431sulfatidelipid raftssphingolipidmyelinmultiple sclerosis |
| spellingShingle | Elizabeth Dustin Edna Suarez-Pozos Camryn Stotesberry Shulan Qiu Juan Pablo Palavicini Xianlin Han Jeffrey L. Dupree Compromised Myelin and Axonal Molecular Organization Following Adult-Onset Sulfatide Depletion Biomedicines sulfatide lipid rafts sphingolipid myelin multiple sclerosis |
| title | Compromised Myelin and Axonal Molecular Organization Following Adult-Onset Sulfatide Depletion |
| title_full | Compromised Myelin and Axonal Molecular Organization Following Adult-Onset Sulfatide Depletion |
| title_fullStr | Compromised Myelin and Axonal Molecular Organization Following Adult-Onset Sulfatide Depletion |
| title_full_unstemmed | Compromised Myelin and Axonal Molecular Organization Following Adult-Onset Sulfatide Depletion |
| title_short | Compromised Myelin and Axonal Molecular Organization Following Adult-Onset Sulfatide Depletion |
| title_sort | compromised myelin and axonal molecular organization following adult onset sulfatide depletion |
| topic | sulfatide lipid rafts sphingolipid myelin multiple sclerosis |
| url | https://www.mdpi.com/2227-9059/11/5/1431 |
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