Elucidating the Mechanisms of Multiple Sclerosis

Immunopathology

Multiple Sclerosis (MS) is a debilitating neurologic disease affecting young adults. A central issue for treatment is how cell signaling pathways regulate oligodendrocyte cell survival and remyelination after the inflammatory response. Oligodendrocytes are the myelinating cells of the central nervous system (CNS); their fine-tuning and survival is paramount for normal neurological function.

Toward this goal, the laboratory of Bridget Shafit-Zagardo, PhD, has used a molecular approach to identify several genes implicated in signaling pathways that regulate oligodendrocyte and neuronal survival. One group of genes encodes proteins belonging to the Tyro3/Axl/Mer (TAM) family of receptor tyrosine kinases. TAM are located at the cell surface and bind the growth factor growth arrest-specific protein 6 (Gas6). Gas6 binding serves as a signal that activates downstream signaling proteins that have multiple functions in the oligodendrocyte, including protection of oligodendrocytes from cell death via the PI3 kinase/AKT pathway. Gas6 signaling is involved in clearance of apoptotic cells and myelin debris following an immune attack. In established MS lesions, increased protease activity upregulates Axl and Mer and negatively correlates with Gas6, reducing the interaction of Gas6 with surface-bound receptors.

Dr. Shafit-Zagardo and her team have initiated in vivo studies to determine whether Gas6 is therapeutic following an inflammatory attack in the CNS in mouse models of neuroimmune demyelination. They are also examining the role of AKT3 in the CNS and in T-cell cell function.

Other ongoing projects involve applying techniques of molecular & cell biology, biochemistry, immunocytochemistry, confocal and electron microscopy to address questions concerning the structure, function and regulation of myelination in the normal CNS and remyelination following neuroimmune injury.