Pathogenesis of Permanent Neurological Disability in Multiple Sclerosis - Project Summary Multiple sclerosis (MS), an immune-mediated demyelinating disease of the human central nervous system, afflicts over 2.5 million people worldwide and is the leading cause of non-traumatic neurological disability in young adults. Most people with MS (PwMS) have a clinical course initially characterized by relapses and remissions (RRMS) that eventually evolves into a progressive course (PMS) where relapses are rare, and disability progression is continuous and irreversible. While it is usually assumed that neurodegeneration results from demyelination, accumulating evidence supports the concept that disability worsening in MS is caused by an insidious neurodegenerative process that can occur independent of relapses and cerebral white matter (WM) demyelination. One intriguing mechanism for neurodegeneration independent of demyelination is surface-in gradients of brain pathology identified by brain imaging studies of PwMS and pathological studies of postmortem MS brains. The main objective of this proposal is to identify cellular and molecular alterations in postmortem MS brains that are responsible for surface-in gradients of myelinated fiber degeneration at the posterior horn of the lateral ventricle, and neuronal and synaptic loss at the pial surface of the cerebral cortex. We recently described a surface-in gradient of myelinated axonal degeneration at the occipital horn of the lateral ventricle. Preliminary studies identified transcript alterations in ependymal cells from postmortem MS brains that correlate with pathological changes that compromise this ependymal cell barrier, identified increased cerebrospinal fluid (CSF) proteins from progressive MS patients that bind to the upregulated ependymal cell surface receptors, and identified a surface-in gradient of oligodendrocyte pathology. Specific Aim 1 will extend these observations by investigating whether a surface-in gradient of oligodendrocyte transcript changes occurs, whether oligodendrocytes express receptors for increased CSF components, and if increased CSF components with ependymal and oligodendrocyte receptors compromise ependymal cells and/or oligodendrocytes in vitro. A surface-in gradient is a likely explanation for the global nature of cortical atrophy found in most PwMS. While pathological and brain imaging studies have identified cortical surface-in gradients, molecular characterization of the mechanism causing this gradient has not been reported. Specific Aim 2 will investigate if pial matter transcripts are altered in MS brain, and whether CSF from PwMS contain upregulated proteins that bind to pial surface proteins. The human cerebral cortex contains a unique population of subpial interlaminar astrocytes that reside in cortical layer I and send multiple apical processes to the pial surface and multiple basal processes that descend into cortical layers II-IV and often associate with activated astrocytes that are associated with cortical vessels. Since these cells are positioned for long-distance communication between CSF and intracortical cells, we will investigate pathological and transcriptional changes in interlaminar astrocytes in MS cortex.
