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Tau‐induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila

The nucleus is a spherical dual‐membrane bound organelle that encapsulates genomic DNA. In eukaryotes, messenger RNAs (mRNA) are transcribed in the nucleus and transported through nuclear pores into the cytoplasm for translation into protein. In certain cell types and pathological conditions, nuclei...

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Autores principales: Cornelison, Garrett L., Levy, Simon A., Jenson, Tyler, Frost, Bess
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351838/
https://www.ncbi.nlm.nih.gov/pubmed/30411463
http://dx.doi.org/10.1111/acel.12847
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author Cornelison, Garrett L.
Levy, Simon A.
Jenson, Tyler
Frost, Bess
author_facet Cornelison, Garrett L.
Levy, Simon A.
Jenson, Tyler
Frost, Bess
author_sort Cornelison, Garrett L.
collection PubMed
description The nucleus is a spherical dual‐membrane bound organelle that encapsulates genomic DNA. In eukaryotes, messenger RNAs (mRNA) are transcribed in the nucleus and transported through nuclear pores into the cytoplasm for translation into protein. In certain cell types and pathological conditions, nuclei harbor tubular invaginations of the nuclear envelope known as the “nucleoplasmic reticulum.” Nucleoplasmic reticulum expansion has recently been established as a mediator of neurodegeneration in tauopathies, including Alzheimer's disease. While the presence of pore‐lined, cytoplasm‐filled, nuclear envelope invaginations has been proposed to facilitate the rapid export of RNAs from the nucleus to the cytoplasm, the functional significance of nuclear envelope invaginations in regard to RNA export in any disorder is currently unknown. Here, we report that polyadenylated RNAs accumulate within and adjacent to tau‐induced nuclear envelope invaginations in a Drosophila model of tauopathy. Genetic or pharmacologic inhibition of RNA export machinery reduces accumulation of polyadenylated RNA within and adjacent to nuclear envelope invaginations and reduces tau‐induced neuronal death. These data are the first to point toward a possible role for RNA export through nuclear envelope invaginations in the pathogenesis of a neurodegenerative disorder and suggest that nucleocytoplasmic transport machinery may serve as a possible novel class of therapeutic targets for the treatment of tauopathies.
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spelling pubmed-63518382019-02-07 Tau‐induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila Cornelison, Garrett L. Levy, Simon A. Jenson, Tyler Frost, Bess Aging Cell Short Take The nucleus is a spherical dual‐membrane bound organelle that encapsulates genomic DNA. In eukaryotes, messenger RNAs (mRNA) are transcribed in the nucleus and transported through nuclear pores into the cytoplasm for translation into protein. In certain cell types and pathological conditions, nuclei harbor tubular invaginations of the nuclear envelope known as the “nucleoplasmic reticulum.” Nucleoplasmic reticulum expansion has recently been established as a mediator of neurodegeneration in tauopathies, including Alzheimer's disease. While the presence of pore‐lined, cytoplasm‐filled, nuclear envelope invaginations has been proposed to facilitate the rapid export of RNAs from the nucleus to the cytoplasm, the functional significance of nuclear envelope invaginations in regard to RNA export in any disorder is currently unknown. Here, we report that polyadenylated RNAs accumulate within and adjacent to tau‐induced nuclear envelope invaginations in a Drosophila model of tauopathy. Genetic or pharmacologic inhibition of RNA export machinery reduces accumulation of polyadenylated RNA within and adjacent to nuclear envelope invaginations and reduces tau‐induced neuronal death. These data are the first to point toward a possible role for RNA export through nuclear envelope invaginations in the pathogenesis of a neurodegenerative disorder and suggest that nucleocytoplasmic transport machinery may serve as a possible novel class of therapeutic targets for the treatment of tauopathies. John Wiley and Sons Inc. 2018-11-09 2019-02 /pmc/articles/PMC6351838/ /pubmed/30411463 http://dx.doi.org/10.1111/acel.12847 Text en © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. 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 Short Take
Cornelison, Garrett L.
Levy, Simon A.
Jenson, Tyler
Frost, Bess
Tau‐induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila
title Tau‐induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila
title_full Tau‐induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila
title_fullStr Tau‐induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila
title_full_unstemmed Tau‐induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila
title_short Tau‐induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila
title_sort tau‐induced nuclear envelope invagination causes a toxic accumulation of mrna in drosophila
topic Short Take
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351838/
https://www.ncbi.nlm.nih.gov/pubmed/30411463
http://dx.doi.org/10.1111/acel.12847
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