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Neuronal RNA‐binding protein dysfunction in multiple sclerosis cortex

OBJECTIVE: Neurodegeneration 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...

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Autores principales: Salapa, Hannah E., Hutchinson, Catherine, Popescu, Bogdan F., Levin, Michael C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359129/
https://www.ncbi.nlm.nih.gov/pubmed/32608162
http://dx.doi.org/10.1002/acn3.51103
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author Salapa, Hannah E.
Hutchinson, Catherine
Popescu, Bogdan F.
Levin, Michael C.
author_facet Salapa, Hannah E.
Hutchinson, Catherine
Popescu, Bogdan F.
Levin, Michael C.
author_sort Salapa, Hannah E.
collection PubMed
description OBJECTIVE: Neurodegeneration 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. METHODS: Cortical 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. RESULTS: Analyses 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). INTERPRETATION: The 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.
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spelling pubmed-73591292020-07-17 Neuronal RNA‐binding protein dysfunction in multiple sclerosis cortex Salapa, Hannah E. Hutchinson, Catherine Popescu, Bogdan F. Levin, Michael C. Ann Clin Transl Neurol Research Articles OBJECTIVE: Neurodegeneration 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. METHODS: Cortical 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. RESULTS: Analyses 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). INTERPRETATION: The 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. John Wiley and Sons Inc. 2020-07-01 /pmc/articles/PMC7359129/ /pubmed/32608162 http://dx.doi.org/10.1002/acn3.51103 Text en © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Salapa, Hannah E.
Hutchinson, Catherine
Popescu, Bogdan F.
Levin, Michael C.
Neuronal RNA‐binding protein dysfunction in multiple sclerosis cortex
title Neuronal RNA‐binding protein dysfunction in multiple sclerosis cortex
title_full Neuronal RNA‐binding protein dysfunction in multiple sclerosis cortex
title_fullStr Neuronal RNA‐binding protein dysfunction in multiple sclerosis cortex
title_full_unstemmed Neuronal RNA‐binding protein dysfunction in multiple sclerosis cortex
title_short Neuronal RNA‐binding protein dysfunction in multiple sclerosis cortex
title_sort neuronal rna‐binding protein dysfunction in multiple sclerosis cortex
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359129/
https://www.ncbi.nlm.nih.gov/pubmed/32608162
http://dx.doi.org/10.1002/acn3.51103
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