Antibodies to the RNA-binding protein hnRNP A1 contribute to neurodegeneration in a model of central nervous system autoimmune inflammatory disease

Abstract

BackgroundNeurodegeneration is believed to be the primary cause of permanent, long-term disability in patients with multiple sclerosis. The cause of neurodegeneration in multiple sclerosis appears to be multifactorial. One mechanism that has been implicated in the pathogenesis of neurodegeneration in multiple sclerosis is the targeting of neuronal and axonal antigens by autoantibodies. Multiple sclerosis patients develop antibodies to the RNA-binding protein, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), which is enriched in neurons. We hypothesized that anti-hnRNP A1 antibodies would contribute to neurodegeneration in an animal model of multiple sclerosis.MethodsFollowing induction of experimental autoimmune encephalomyelitis (EAE) by direct immunization with myelin oligodendrocyte glycoprotein, mice were injected with anti-hnRNP A1 or control antibodies. Animals were examined clinically, and the central nervous system (CNS) tissues were tested for neurodegeneration with Fluoro-Jade C, a marker of degenerating neural elements.ResultsInjection of anti-hnRNP A1 antibodies in mice with EAE worsened clinical disease, altered the clinical disease phenotype, and caused neurodegeneration preferentially in the ventral spinocerebellar tract and deep white matter of the cerebellum in the CNS. Neurodegeneration in mice injected with hnRNP A1-M9 antibodies compared to control groups was consistent with “dying back” axonal degeneration.ConclusionsThese data suggest that antibodies to the RNA-binding protein hnRNP A1 contribute to neurodegeneration in immune-mediated disease of the CNS.

Dysfunctional RNA‐binding protein biology and neurodegeneration in experimental autoimmune encephalomyelitis in female mice

“…Several mechanisms of neurodegeneration have been observed in MS, including axonal transport deficits, mitochondrial dysfunction, and the humoral immune response (Benarroch, 2015;Campbell et al, 2011;Coleman, 2005;De Vos, Grierson, Ackerley, & Miller, 2008;Dutta et al, 2006;Huizinga, Gerritsen, Heijmans, & Amor, 2008;Mathey et al, 2007;Nikic et al, 2011). Additionally, autoantibodies to heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), an RNA-binding protein (RBP), have been identified in MS patients and are implicated in neuronal dysfunction and damage (Douglas et al, 2016;Lee et al, 2011;Levin et al, 2002). Additionally, autoantibodies to heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), an RNA-binding protein (RBP), have been identified in MS patients and are implicated in neuronal dysfunction and damage (Douglas et al, 2016;Lee et al, 2011;Levin et al, 2002).…”

“…Interestingly, administration of antibodies to non-myelin antigens, such as neurofascin and neurofilament, in experimental autoimmune encephalomyelitis (EAE) models leads to axonal and neuronal injury (Huizinga et al, 2008;Mathey et al, 2007). Additionally, autoantibodies to heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), an RNA-binding protein (RBP), have been identified in MS patients and are implicated in neuronal dysfunction and damage (Douglas et al, 2016;Lee et al, 2011;Levin et al, 2002).…”

Heterogeneous Nuclear Ribonucleoproteins: Implications in Neurological Diseases

“…It was found that hnRNP A1 binds to spastin, a gene responsible for hereditary spastic paraparesis, which produces a phenotype that is closely similar to MS [162]. This finding was also replicated by another group which found a hnRNP A1 antibodies in animal models also contributed to neurodegeneration as evidenced by increased localization to stress granules, worsened experimental autoimmune encephalomyelitis (EAE) cases, modifications in phenotype from flaccid to spastic paralysis, and selective degeneration in the cerebellar white matter [166].…”

Monoclonal antibody against H1N1 influenza virus hemagglutinin cross reacts with hnRNPA1 and hnRNPA2/B1

“…Levin et al (20) revealed that autoantibodies to hnRNPA1 may cause neurodegenerative changes. Animal experiments have demonstrated that hnRNPA1 antibodies are associated with multiple sclerosis (21). Sueoka et al (22) detected antibodies in the cerebrospinal fluid of 35 patients with multiple sclerosis and reported that 32 of them had antibodies against the hnRNPB1 protein.…”