Neuronal RNA-binding protein dysfunction in multiple sclerosis cortex.

Hannah E Salapa,Bogdan F Popescu,Catherine Hutchinson,Michael C Levin

doi:10.1002/acn3.51103

Hannah E Salapa, Bogdan F Popescu + Show 2 more

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https://doi.org/10.1002/acn3.51103

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Abstract

ObjectiveNeurodegeneration is thought to be the primary cause of neurological disability in multiple sclerosis (MS). Dysfunctional RNA‐binding proteins (RBPs) including their mislocalization from nucleus to cytoplasm, stress granule formation, and altered RNA metabolism have been found to underlie neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia. Yet, little is known about the role of dysfunctional RBPs in the pathogenesis of neurodegeneration in MS. As a follow‐up to our seminal finding of altered RBP function in a single case of MS, we posited that there would be evidence of RBP dysfunction in cortical neurons in MS.MethodsCortical neurons from 12 MS and six control cases were analyzed by immunohistochemistry for heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and TAR‐DNA‐binding protein‐43 (TDP‐43). Seven distinct neuronal phenotypes were identified based on the nucleocytoplasmic staining of these RBPs. Statistical analyses were performed by analyzing each phenotype in relation to MS versus controls.ResultsAnalyses revealed a continuum of hnRNP A1 and TDP‐43 nucleocytoplasmic staining was found in cortical neurons, from neurons with entirely nuclear staining with little cytoplasmic staining in contrast to those with complete nuclear depletion of RBPs concurrent with robust cytoplasmic staining. The neuronal phenotypes that showed the most nucleocytoplasmic mislocalization of hnRNP A1 and TDP‐43 statistically distinguished MS from control cases (P < 0.01, P < 0.001, respectively).InterpretationThe discovery of hnRNP A1 and TDP‐43 nucleocytoplasmic mislocalization in neurons in MS brain demonstrate that dysfunctional RBPs may play a role in neurodegeneration in MS, as they do in other neurological diseases.

Highlights

Multiple sclerosis (MS) is a demyelinating autoimmune disorder of the central nervous system (CNS) in which neurodegeneration plays a significant role in its pathogenesis
In order to account for the varying degrees of mislocalization, we described seven neuronal RNA-binding proteins (RBPs) phenotypes to stage TDP43 localization in this study (Table 2, Fig. 1)
We previously published data from a single multiple sclerosis (MS) case compared to a non-MS control demonstrating nuclear depletion of hnRNP A1, an RBP important in mRNA splicing and transport.[2]

Summary

Introduction

Multiple sclerosis (MS) is a demyelinating autoimmune disorder of the central nervous system (CNS) in which neurodegeneration plays a significant role in its pathogenesis. One of the key pathological features of MS is the development of demyelinated lesions or plaques in the CNS. Plaques, depending on their stage, can contain numerous immune cells, including T cells and macrophages. Lesions show evidence of axonal injury.[1] Multiple mechanisms underlying neurodegeneration in MS have been proposed, including axonal transport deficits, mitochondrial dysfunction, and autoantibodies to nonmyelin antigens. We have provided evidence from a single MS case that a novel mechanism may underlie neuronal damage in MS.[2] We have shown neuronal mislocalization of the RNAbinding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) from its homeostatic nuclear location to the cytoplasm, where it forms aggregates. We have found that these hnRNP A1 cytoplasmic accumulations colocalize with a marker of stress granules

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