Date of Award
Doctor of Philosophy (PhD)
Michael C. Levin, M.D.
William Armstrong, Ph.D. Lidia Gardner, Ph.D. Ramin Homayouni, Ph.D. Richard J. Smeyne, Ph.D.
Multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system. MS is believed to occur in genetically susceptible individuals due to an unknown environmental stimulus. MS patients produce autoantibodies to heterogenous nuclear ribonuclearprotein A1 (hnRNP A1), an RNA binding protein (RBP) highly expressed in neurons. hnRNP A1 functions in pre-mRNA splicing, mRNA trafficking, and translation. Furthermore, the anti-hnRNP A1 antibodies are specific to a N-terminal region termed ‘M9’ which serves as a nuclear export sequence/nuclear localization sequence (NES/NLS) responsible for nuclear/cytoplasmic transport of the protein. In this manuscript we will provide data revealing that anti-hnRNP A1 antibodies enter neuronal cells via clathrin-mediated endocytosis. Moreover, we have shown that anti-hnRNP A1 antibodies cause redistribution of endogenous hnRNP A1 protein, decrease in cellular ATP levels, and increase in apoptosis. Additionally, we present data depicting RNA binding partners of hnRNP A1 protein as well as the effect of anti-hnRNP A1 autoantibodies upon specific RNA binding partners. To further these studies we set out to determine the effect of anti-hnRNP A1 antibodies on experimental autoimmune encephalomyelitis (EAE), the murine model of MS. Specifically, we will present the effect of anti-hnRNP A1-M9 antibodies on clinical symptoms and neurodegeneration in EAE. Taken together, we present a series of experiments which will depict a journey of discovery from the initial discovery of anti-hnRNP A1 antibodies to our present understanding of trafficking, deleterious effects, and in vivo effects of anti-hnRNP A1 antibodies and their implications in the disease Multiple Sclerosis.
Douglas, Joshua Nathan (http://orcid.org/0000-0001-5140-0133), "Antibodies to Heterogenous Nuclear Ribonucleoprotein A1 Penetrate Neurons Leading to Multiple Downstream Effects Resulting in Neurodegeneration" (2016). Theses and Dissertations (ETD). Paper 391. http://dx.doi.org/10.21007/etd.cghs.2016.0402.
Available for download on Friday, June 23, 2017