Pathogenic mechanisms of neurodegeneration based on the phenotypic expression of progressive forms of immune-mediated neurologic disease

Abstract

Considering there are no treatments for progressive forms of multiple sclerosis (MS), a comprehensive understanding of the role of neurodegeneration in the pathogenesis of MS should lead to novel therapeutic strategies to treat it. Many studies have implicated viral triggers as a cause of MS, yet no single virus has been exclusively shown to cause MS. Given this, human and animal viral models of MS are used to study its pathogenesis. One example is human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Importantly, HAM/TSP is similar clinically, pathologically, and immunologically to progressive MS. Interestingly, both MS and HAM/TSP patients were found to make antibodies to heterogeneous nuclear ribonucleoprotein (hnRNP) A1, an RNA-binding protein overexpressed in neurons. Anti-hnRNP A1 antibodies reduced neuronal firing and caused neurodegeneration in neuronal cell lines, suggesting the autoantibodies are pathogenic. Further, microarray analyses of neurons exposed to anti-hnRNP A1 antibodies revealed novel pathways of neurodegeneration related to alterations of RNA levels of the spinal paraplegia genes (SPGs). Mutations in SPGs cause hereditary spastic paraparesis, genetic disorders clinically indistinguishable from progressive MS and HAM/TSP. Thus, there is a strong association between involvement of SPGs in neurodegeneration and the clinical phenotype of progressive MS and HAM/TSP patients, who commonly develop spastic paraparesis. Taken together, these data begin to clarify mechanisms of neurodegeneration related to the clinical presentation of patients with chronic immune-mediated neurological disease of the central nervous system, which will give insights into the design of novel therapies to treat these neurological diseases.

Antibodies to Heterogenous Nuclear Ribonucleoprotein A1 Penetrate Neurons Leading to Multiple Downstream Effects Resulting in Neurodegeneration

“…189,190 Pathologically, accumulation of amyloid precursor protein (APP) 15,191 and staining for non-phosphorylated neurofilament (SMI-32) 9 (both markers of axonal injury) showed that axonal damage is a major component of MS lesions. 9,187,192,193 Importantly, several studies have shown the presence of neurodegeneration throughout the disease course of MS, not just during latter progressive phases of disease, as was originally thought. 187 In experimental allergic encephalomyelitis (EAE), an animal model of MS, data indicate that (like in MS) neuronal and axonal damage are present throughout the course of the disease, and thus contribute to the neurologic disability displayed by the animals.…”

“…spastic paraparesis and ataxia). 11,12,192 In separate in vitro experiments, anti-hnRNP A1 antibodies were found to enter neurons by utilizing endocytosis, a mechanism identical to antibodies isolated from ALS patients and monoclonal antibodies directed at Tau protein. 11,[206][207][208] Further, the anti-hnRNP A1 antibodies caused the mis-localization of hnRNP A1 from predominantly nuclear to an equal nuclear/cytoplasmic distribution suggesting that the anti-hnRNP a1 antibodies bound M9 and disrupted hnRNP A1's normal trafficking between the nucleus and cytoplasm.…”

“…Thus, anti-hnRNP A1 antibodies bind M9, which causes mislocalization of hnRNP A1 to the neuronal cytoplasm, SG formation, translational repression of RNA bound to hnRNP A1 and subsequent neurodegeneration. 1, 2,11,12,95,99 It is important to note that mutations in the genes affected (SPG4, SPG7) result in various forms of HSP. 133 HSP is a genetically inherited spastic disorder similar clinically to MS. 133 Mutations in SPG4 account for the most common autosomal dominant form of HSP.…”

“…112,202 MS patients (in contrast to healthy controls) have also been found to have antibodies to hnRNP A1, a ubiquitously expressed RNA binding protein (RBP) that is over expressed in neurons. 11,12,94,95,192,193 Importantly, RBPs including hnRNP A1 regulate RNA metabolism and dysfunctional RBPs have been shown to cause neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobe dementia (FTLD). 132,184,203 The immunodominant epitope of hnRNP A1 recognized by MS IgG was experimentally determined to include 'M9', hnRNP A1's nucleocytoplasmic shuttling domain, which is required for its transport into and out of the nucleus to the cytoplasm.…”

“…These data add to the growing body of evidence that EAE is a suitable animal model to study neurodegeneration mechanisms that may be applicable to MS. 148,194,195,[223][224][225] Neurodegeneration is now believed to be the primary cause of permanent, longterm disability in MS patients. 187,188,192,193 Data indicate neuronal and axonal damage in an ongoing process in MS. 7,9,13,186,187 In some patients, it begins during the relapsing, remitting phase of MS (RRMS) and continues into secondary progressive MS (SPMS). Neurodegeneration is also a common feature in MS patients without relapses (primary progressive MS (PPMS).…”