Loss of neurons and axons, collectively known as neurodegeneration, is characteristic of multiple sclerosis (MS), correlating with permanent disability. Dysfunctional RNA binding proteins (RBPs) underlie neurodegeneration in neurological diseases. Features of RBP dysfunction include mislocalization from its homeostatic nuclear location to the cytoplasm and formation of cytoplasmic stress granules (SGs). Neurons in MS brains display characteristic features of heterogenous nuclear ribonucleoprotein A1 (A1) dysfunction including its cytoplasmic mislocalization and depletion from the nucleus. Further, MS patients make antibodies to A1, and injections of anti-A1 antibodies into mice with experimental autoimmune encephalomyelitis (EAE – an animal model of MS) resulted in increased neurodegeneration.
To determine how A1 dysfunction and anti-A1 antibodies contribute mechanistically to disease progression and NDG in an animal model of MS.
EAE was induced by immunization with myelin oligodendrocyte glycoprotein35-55. At symptom onset, mice were injected with anti-A1 antibodies or saline (control). Mice were sacrificed at five timepoints over a 21-day time course. Tissue was analyzed quantitatively for A1 mislocalization, SGs and neuronal loss (a marker of neurodegeneration) by immunohistochemistry.
Mice in the EAE control group displayed neuronal A1 mislocalization (p<0.0001) and SG formation (p<0.01), which peaked at symptom onset concurrent with neuronal loss (p<0.01). After symptom onset, A1 mislocalization, SG formation returned to pre-symptomatic levels. Injections of anti-A1 antibodies into mice with EAE resulted in greater disability (p<0.05) and exacerbation of neuronal A1 mislocalization (p<0.05) and SG formation (p<0.05), including nuclear depletion of A1 (p<0.0001), a pathogenic neuronal phenotype in MS brains. These findings preceded neuronal cell loss. The anti-A1 antibodies also exacerbated neuronal cell loss (p<0.05), which did not recover and continued until the 21-day time point.
In contrast to controls, EAE mice injected with anti-A1 antibodies showed that RBP dysfunction occurred prior to neuronal cell body death (a marker of neurodegeneration) indicative of A1 dysfunction triggering, rather than resulting from neurodegeneration. The antibodies also exacerbated and caused permanent neuronal damage. These data reveal a novel mechanism of neurodegeneration, which can be targeted to inhibit disability in MS.