title: Antibodies to the RNA Binding Protein Heterogeneous Nuclear Ribonucleoprotein A1 Colocalize to Stress Granules Resulting in Altered RNA and Protein Levels in a Model of Neurodegeneration in Multiple Sclerosis.
abstract: OBJECTIVE
  Multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system (CNS). Data suggest that antibodies to CNS targets contribute to the pathogenesis of MS. MS patients produce autoantibodies to heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1). hnRNP A1 is an RNA binding protein (RBP) overexpressed in neurons that functions in pre-mRNA splicing, mRNA trafficking, and translation. Previously, we showed that anti-hnRNP A1 antibodies entered neuronal cells (in vitro)viaclathrin-mediated endocytosis, caused mislocalization of endogenous hnRNP A1 protein and increased markers of neurodegeneration including decreased ATP concentration and apoptosis. In this study, we hypothesized that anti-hnRNP A1 antibodies might cause stress granule formation and altered levels of RNAs and proteins that bind hnRNP A1.
  
  
  METHODS
  Neuronal cell lines were exposed to anti-hnRNP A1 and isotype-matched control antibodiesin vitroand examined for neuronal granule formation, including stress granules, P bodies and transport granules. In addition, RNAs that bound hnRNP A1 were determined. Levels of RNA and their translated proteins were measured upon exposure to the anti-hnRNP A1 antibodies.
  
  
  RESULTS
  Anti-hnRNP A1 antibodies induced and localized to stress granules, a marker of neurodegeneration, within a neuronal cell line. The anti-hnRNP A1 antibodies did not induce P bodies or neuronal granules. Clinically relevant RNAs were found to bind hnRNP A1. In addition, the anti-hnRNP A1 antibodies caused reduced levels of RNA and protein of the spinal paraplegia genes (SPGs) 4 and 7, which when mutated mimic progressive MS.
  
  
  CONCLUSIONS
  Taken together, these data suggest potential mechanisms by which autoantibodies may contribute to neurodegeneration in MS.
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, 38104, USA; Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Douglas
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, 38104, USA; Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Lidia A
authors.initials: LA
authors.lastname: Gardner
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, 38104, USA; Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Salapa
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, 38104, USA; Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Research Service, VA Medical Center, Memphis, TN, 38104, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Levin
keywords: Multiple sclerosis; Neurodegeneration; RNA binding protein; Spastin; Stress granules; hnRNP A1