| Autor: |
Dustin E; Research Service, Richmond Veterans Affairs Medical Center, Central Virginia Veterans Affairs Health Care System, Richmond, VA 23249, USA.; Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond VA 23298, USA., Suarez-Pozos E; Research Service, Richmond Veterans Affairs Medical Center, Central Virginia Veterans Affairs Health Care System, Richmond, VA 23249, USA.; Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond VA 23298, USA., Stotesberry C; Department of Biology, Virginia Commonwealth University, Richmond, VA 23298, USA., Qiu S; Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.; Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA., Palavicini JP; Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.; Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA., Han X; Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.; Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA., Dupree JL; Research Service, Richmond Veterans Affairs Medical Center, Central Virginia Veterans Affairs Health Care System, Richmond, VA 23249, USA.; Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond VA 23298, USA. |
| Abstrakt: |
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. |
