Abstract Details

Neurodegeneration, the progressive loss or damage to neurons and axons, underlies permanent disability in MS; yet its mechanisms are incompletely understood. MS patients make autoantibodies to and display features of dysfunctional heterogenous nuclear ribonucleoprotein A1 (A1), an RBP overexpressed in neurons. Previously we identified that A1 antibodies induce RBP dysfunction and neurodegeneration, but it’s unknown whether A1 dysfunction triggers or occurs because of neurodegeneration.

To determine the contribution of autoimmune induced RNA binding protein (RBP) dysfunction to neurodegeneration in a model of multiple sclerosis (MS).

A1 antibodies (overlapping with the immunodominant epitope of MS IgG) were injected into mice with experimental autoimmune encephalomyelitis. Spinal cord neurons were analyzed for markers of RBP dysfunction and neurodegeneration over time (7-, 15- and 21-days following onset of disease). RNA sequencing was performed on spinal cord grey matter to study A1 antibody induced changes in RNA metabolism. Mice were scored daily using a validated clinical disability scale.

Compared to controls, A1 antibody treatment resulted in an exacerbation of A1 dysfunction, including an (i) increase in A1 mislocalization and nuclear depletion at days 7 and 15 (*p < .05), (ii) alteration in RNA metabolism at day 15, and (iii) increase in stress granule formation at days 15 and 21(*p < .01). RNA sequencing identified 816 differentially expressed genes (546 of which have been identified to bind A1) and enrichment of pathways related to cell stress and programmed cell death. These molecular changes preceded exacerbated clinical disease, and an increase in necroptotic signalling (*p < .01) and neurodegeneration at day 21 (*p < .001), indicative of A1 dysfunction causing, rather than being a consequence of, neurodegeneration.

These data identify a novel autoimmune-mediated mechanism of neuronal cell death which exacerbates clinical disability and may be targeted to prevent neurological decline in MS.