Dysfunctional RNA binding protein biology in autoimmune disease of the central nervous system
| dc.contributor.advisor | Levin, Michael C | |
| dc.contributor.committeeMember | Verge, Valerie | |
| dc.contributor.committeeMember | Popescu, Bogdan | |
| dc.contributor.committeeMember | Chlan-Fourney, Jennifer | |
| dc.contributor.committeeMember | Gordon, John | |
| dc.creator | Salapa, Hannah Elizabeth 1993- | |
| dc.date.accessioned | 2019-07-09T21:29:26Z | |
| dc.date.available | 2020-07-09T06:05:09Z | |
| dc.date.created | 2019-06 | |
| dc.date.issued | 2019-07-09 | |
| dc.date.submitted | June 2019 | |
| dc.date.updated | 2019-07-09T21:29:26Z | |
| dc.description.abstract | Dysfunctional RNA binding proteins (RBP) have been shown to contribute to neurological conditions, including amyotrophic lateral sclerosis, frontotemporal dementia, and Alzheimer’s disease. Pathological features associated with dysfunctional RBPs in these diseases include RBP mislocalization from its normal nuclear location to the cytoplasm, the formation of chronic stress granules (SGs), and altered RNA metabolism. We have previously shown that multiple sclerosis (MS) patients make antibodies to the RBP, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1). Addition of anti-hnRNP A1 antibodies to neuronal cell lines in vitro results in hnRNP A1 mislocalization to the cytoplasm, SG formation, and alterations in key RNA transcripts. Furthermore, addition of these antibodies to animals with experimental autoimmune encephalomyelitis (EAE) results in worsened disease and preferential neurodegeneration in specific central nervous system areas. We hypothesized that dysfunctional RBP biology may also result from cytokines in addition to antibody exposure. We tested this hypothesis by examining dysfunctional RBP neuronal biology in neuronal cell lines, EAE, and human MS tissue. We found that exposure of a neuronal cell line to the pro-inflammatory cytokine, IFN-gamma resulted in hnRNP A1 mislocalization, persistent SG formation, and disrupted translation in SG+ cells. In mice with EAE, we observed hnRNP A1 mislocalization and SG formation, both of which positively correlated with clinical score. Furthermore, EAE animals injected with anti-hnRNP A1 antibodies showed a greater degree of neuronal hnRNP A1 mislocalization than EAE animals injected with IgG control antibodies or saline control (p<0.05). Finally, we found evidence of dysfunctional RBP biology in MS tissue, including a greater degree of hnRNP A1 mislocalization (p<0.0001) and SG formation (p<0.05) in neurons in MS brains compared to control brains. These findings suggest that dysfunctional RBP biology is influenced by the pro-inflammatory cytokine IFN-gamma and anti-hnRNP A1 antibodies, which appear to be contributing to dysfunctional RBP biology observed in EAE animals and MS tissue. We have potentially identified a novel mechanism underlying neuronal damage and death in autoimmune disease of the central nervous system. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/10388/12172 | |
| dc.subject | RNA binding protein | |
| dc.subject | hnRNP A1 | |
| dc.subject | Multiple Sclerosis | |
| dc.title | Dysfunctional RNA binding protein biology in autoimmune disease of the central nervous system | |
| dc.type | Thesis | |
| dc.type.material | text | |
| local.embargo.terms | 2020-07-09 | |
| thesis.degree.department | Anatomy and Cell Biology | |
| thesis.degree.discipline | Anatomy and Cell Biology | |
| thesis.degree.grantor | University of Saskatchewan | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) |