Contribution of a Dysfunctional RNA Binding Protein, hnRNP A1, to Neurodegeneration in MS (S14.003)

OBJECTIVE: To evaluate the potential role of RNA binding protein heterogeneous nuclear ribonuclear protein A1 (hnRNP A1) dysfunction in the pathogenesis of neuronal death and neurodegeneration in, multiple sclerosis (MS). BACKGROUND: Mutations in the genetic sequence of hnRNP A1 isolated from amyotrophic lateral sclerosis (ALS) patients were associated with abnormal function of hnRNP A1, suggesting that mutant hnRNP A1 contributes to neurodegeneration in ALS (Nature 495, 2013). Importantly, MS patients make antibodies to hnRNP A1. IgG binding was specific for hnRNP A1-M9, its nucleocytoplasmic transport sequence, which binds transportin and is required for mRNA transport (J Neuroimmunology 235, 2011. J Clin Cell Immunol 4, 2013). DESIGN/METHODS: High fidelity DNA sequencing was used to examine the sequence of hnRNP A1-M9 in human brain and lymphocytes. Mutant and wild type hnRNP A1 were transfected into SKNSH neurons and examined for transportin binding, cell death and RNA expression. MS and control IgG were tested for immunoreactivity to neurons. Mouse models were used to examine the consequences of anti-hnRNP A1 antibody infusion. RESULTS: Mutations were identified within the M9 DNA sequence of hnRNP A1. Compared to wild-type; mutant hnRNP A1-M9 DNA resulted in decreased binding of hnRNP A1 protein to transportin, redistribution of hnRNP A1 within SKNSH neurons, and increased stress granules consistent with apoptosis of SKNSH neurons. PCR array showed differences in genes associated with cell death. MS IgG localized to hnRNP A1 contained within stress granules in neurons. Transferred anti-hnRNP A1 antibodies localized to the brain and spinal cord and induced neurodegeneration in mice. CONCLUSIONS: Mutant hnRNP A1-M9 DNA was identified in MS patients and caused stress and apoptosis in neurons. Anti-hnRNP A1 antibodies promoted neurodegeneration in a mouse model of MS. These data suggest that dysfunction of hnRNP A1, either as a result of genetic mutation or autoimmune targeting, contributes to neurodegeneration in MS. Study Supported by: Office of Research Service, Department of Veterans Affairs. University of Tennessee Multiple Sclerosis Fund Disclosure: Dr. Levin has received personal compensation for activities with Serono Inc., Teva Neuroscience, and Biogen Idec as a speaker, and Gerson Lehman Group and The CME Institute as a consultant. Dr. Lee has nothing to disclose. Dr. Gardner has nothing to disclose. Dr. Douglas has nothing to disclose. Dr. Shin has nothing to disclose. Dr. Sawchenko has nothing to disclose. Dr. Lalor has nothing to disclose. Dr. Segal has received personal compensation for activities with Biogen Idec and Novartis. Dr. Segal has received (royalty or license fee or contractual rights) payments from Vaccinex, Inc. Dr. Segal has received research support from Biogen Idec and Teva Neuroscience.