DOI
https://doi.org/10.25772/3VYF-PD64
Author ORCID Identifier
0000-0002-8198-4587
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Neuroscience
First Advisor
Dr. Jeffrey Dupree
Abstract
Multiple Sclerosis is an immune mediated disease of the CNS. MS is diagnosed through detection of demyelinated regions. However, recent studies demonstrate that Normal Appearing White Matter (NAWM) contains substantial pathology. One such pathology observed in the NAWM is the reduction of sulfatide. The proper stoichiometry of lipids in myelin acts to maintain rapid conduction velocity, provide trophic support to the neuron, and protect the axon from degeneration. We previously characterized a mouse lacking sulfatide’s synthesizing enzyme, CST through constitutive gene disruption and demonstrate that sulfide is required for proper stability of the myelin sheath. However, since MS is typically diagnosed in adults, the constitutive CST KO mouse has limited clinical relevance since these mice lack sulfatide embryonically. To generate a more clinically relevant model, our lab generated a “floxed” CST mouse, mating it to the PLP-creERT driver to provide spatial and temporal ablation of sulfatide. I demonstrate that there is no change in g-ratios or myelin abnormalities, but there is presence of axonal degeneration. In addition, ion channels and Caspr1 become mis-localized, with loss of contactin-neurofascin155 binding. Subsequently, EP activity of myelinated fibers is disrupted. I also demonstrate lack of neurofascin155 stability within the myelin sheath, which is likely due to loss of sulfatide stability. Together, my studies show that adult onset sulfatide depletion is sufficient to drive axonal pathology while maintaining myelin integrity. These findings have significant implications in understanding the clinical presentation of MS indicating that loss of CNS function may precede demyelination in this devastating disease.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-10-2023