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Matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization
Abnormalities in nucleic acid processing are associated with the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in Matrin 3 (MATR3), a poorly understood DNA- and RNA-binding protein, cause familial ALS/FTD, and MATR3 pathology is a feature of sporadic...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050042/ https://www.ncbi.nlm.nih.gov/pubmed/30015619 http://dx.doi.org/10.7554/eLife.35977 |
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author | Malik, Ahmed M Miguez, Roberto A Li, Xingli Ho, Ye-Shih Feldman, Eva L Barmada, Sami J |
author_facet | Malik, Ahmed M Miguez, Roberto A Li, Xingli Ho, Ye-Shih Feldman, Eva L Barmada, Sami J |
author_sort | Malik, Ahmed M |
collection | PubMed |
description | Abnormalities in nucleic acid processing are associated with the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in Matrin 3 (MATR3), a poorly understood DNA- and RNA-binding protein, cause familial ALS/FTD, and MATR3 pathology is a feature of sporadic disease, suggesting that MATR3 dysfunction is integrally linked to ALS pathogenesis. Using a rat primary neuron model to assess MATR3-mediated toxicity, we noted that neurons were bidirectionally vulnerable to MATR3 levels, with pathogenic MATR3 mutants displaying enhanced toxicity. MATR3’s zinc finger domains partially modulated toxicity, but elimination of its RNA recognition motifs had no effect on survival, instead facilitating its self-assembly into liquid-like droplets. In contrast to other RNA-binding proteins associated with ALS, cytoplasmic MATR3 redistribution mitigated neurodegeneration, suggesting that nuclear MATR3 mediates toxicity. Our findings offer a foundation for understanding MATR3-related neurodegeneration and how nucleic acid binding functions, localization, and pathogenic mutations drive sporadic and familial disease. |
format | Online Article Text |
id | pubmed-6050042 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-60500422018-07-18 Matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization Malik, Ahmed M Miguez, Roberto A Li, Xingli Ho, Ye-Shih Feldman, Eva L Barmada, Sami J eLife Cell Biology Abnormalities in nucleic acid processing are associated with the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in Matrin 3 (MATR3), a poorly understood DNA- and RNA-binding protein, cause familial ALS/FTD, and MATR3 pathology is a feature of sporadic disease, suggesting that MATR3 dysfunction is integrally linked to ALS pathogenesis. Using a rat primary neuron model to assess MATR3-mediated toxicity, we noted that neurons were bidirectionally vulnerable to MATR3 levels, with pathogenic MATR3 mutants displaying enhanced toxicity. MATR3’s zinc finger domains partially modulated toxicity, but elimination of its RNA recognition motifs had no effect on survival, instead facilitating its self-assembly into liquid-like droplets. In contrast to other RNA-binding proteins associated with ALS, cytoplasmic MATR3 redistribution mitigated neurodegeneration, suggesting that nuclear MATR3 mediates toxicity. Our findings offer a foundation for understanding MATR3-related neurodegeneration and how nucleic acid binding functions, localization, and pathogenic mutations drive sporadic and familial disease. eLife Sciences Publications, Ltd 2018-07-17 /pmc/articles/PMC6050042/ /pubmed/30015619 http://dx.doi.org/10.7554/eLife.35977 Text en © 2018, Malik et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Malik, Ahmed M Miguez, Roberto A Li, Xingli Ho, Ye-Shih Feldman, Eva L Barmada, Sami J Matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization |
title | Matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization |
title_full | Matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization |
title_fullStr | Matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization |
title_full_unstemmed | Matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization |
title_short | Matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization |
title_sort | matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050042/ https://www.ncbi.nlm.nih.gov/pubmed/30015619 http://dx.doi.org/10.7554/eLife.35977 |
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