To determine if RNA binding proteins (RBPs) contribute to the pathogenesis of neurodegeneration in MS tissue and models of MS.

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.

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).

Neurons from the brains of MS patients (n=14) compared to controls (n=6) showed nuclear depletion and nucleocytoplasmic mislocalization of TDP-43 (p<0.01). A1 showed a similar distribution. Both RBPs colocalized to cytoplasmic SGs in neurons. In SK-N-SH cells, IFNγ caused A1 mislocalization, SG formation and eiF2α phosphorylation, an initiating step of translation. A1 antibodies induced A1 mislocalization, SG formation and metabolism of clinically important RNAs. Mice with EAE showed TDP-43 mislocalization (p<0.001), A1 mislocalization (p<0.05), and SG formation (p<0.0001) of ventral spinal cord gray matter neurons. These areas displayed neuronal loss (p<0.0001) and increased SMI-32 immunoreactivity in areas of IFNγ secreting T-cells. A1 injected antibodies localized to the ventral spinal cord adjacent to and within neurons, exacerbated neuronal cell loss and induced iNOS expression.

These data suggest that dysfunctional RBPs contribute to the pathogenesis of neurodegeneration in MS.