A Role for Dysfunctional RNA Binding Proteins in the Pathogenesis of Neurodegeneration in MS (2669)

Objective: To determine if RNA binding proteins (RBPs) contribute to the pathogenesis of neurodegeneration in MS tissue and models of MS. Background: RBP dysfunction in neurons is demonstrated by their mislocalization from the nucleus to the cytoplasm, co-localization in pathologic stress granules (SGs) and altered RNA metabolism. Recent publications implicate the RBP heterogeneous nuclear ribonucleoprotein A1 (A1) in MS pathogenesis. MS patients make A1 antibodies, injection of A1 antibodies into mice with experimental autoimmune encephalomyelitis (EAE) worsened disease and A1 was mis-localized to the neuronal cytoplasm in MS brains. Considering the role that other RBPs play in neurologic disease, we hypothesized that both A1 and Tar DNA Binding protein-43 (TDP-43) would be altered using models of neurodegeneration. Design/Methods: Quantitative analyses of RBP localization, RNA metabolism, markers for neurodegeneration and SGs were assessed in: MS brains, neuronal cell lines (SK-N-SH) following exposure to cytokines and A1 antibodies, and mice with EAE following injection of A1 antibodies (which overlap the human immunodominant epitope of A1). Results: Neurons from the brains of MS patients (n=14) compared to controls (n=6) showed nuclear depletion and nucleocytoplasmic mislocalization of TDP-43 (p Conclusions: These data suggest that dysfunctional RBPs contribute to the pathogenesis of neurodegeneration in MS. Disclosure: Dr. Levin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BiogenIdec, Merck Manual. Dr. Salapa has nothing to disclose. Dr. Libner has nothing to disclose. Dr. Hutchinson has nothing to disclose. Dr. Popescu has nothing to disclose.