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Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy
Frontotemporal lobar degeneration (FTLD) has been subdivided based on the main pathology found in the brains of affected individuals. When the primary pathology is aggregated, hyperphosphorylated tau, the pathological diagnosis is FTLD-tau. When the primary pathology is cytoplasmic and/or nuclear ag...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer-Verlag
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690181/ https://www.ncbi.nlm.nih.gov/pubmed/23666556 http://dx.doi.org/10.1007/s00401-013-1123-8 |
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author | Clippinger, Amy K. D’Alton, Simon Lin, Wen-Lang Gendron, Tania F. Howard, John Borchelt, David R. Cannon, Ashley Carlomagno, Yari Chakrabarty, Paramita Cook, Casey Golde, Todd E. Levites, Yona Ranum, Laura Schultheis, Patrick J. Xu, Guilian Petrucelli, Leonard Sahara, Naruhiko Dickson, Dennis W. Giasson, Benoit Lewis, Jada |
author_facet | Clippinger, Amy K. D’Alton, Simon Lin, Wen-Lang Gendron, Tania F. Howard, John Borchelt, David R. Cannon, Ashley Carlomagno, Yari Chakrabarty, Paramita Cook, Casey Golde, Todd E. Levites, Yona Ranum, Laura Schultheis, Patrick J. Xu, Guilian Petrucelli, Leonard Sahara, Naruhiko Dickson, Dennis W. Giasson, Benoit Lewis, Jada |
author_sort | Clippinger, Amy K. |
collection | PubMed |
description | Frontotemporal lobar degeneration (FTLD) has been subdivided based on the main pathology found in the brains of affected individuals. When the primary pathology is aggregated, hyperphosphorylated tau, the pathological diagnosis is FTLD-tau. When the primary pathology is cytoplasmic and/or nuclear aggregates of phosphorylated TAR-DNA-binding protein (TDP-43), the pathological diagnosis is FTLD-TDP. Notably, TDP-43 pathology can also occur in conjunction with a number of neurodegenerative disorders; however, unknown environmental and genetic factors may regulate this TDP-43 pathology. Using transgenic mouse models of several diseases of the central nervous system, we explored whether a primary proteinopathy might secondarily drive TDP-43 proteinopathy. We found abnormal, cytoplasmic accumulation of phosphorylated TDP-43 specifically in two tau transgenic models, but TDP-43 pathology was absent in mouse models of Aβ deposition, α-synucleinopathy or Huntington’s disease. Though tau pathology showed considerable overlap with cytoplasmic, phosphorylated TDP-43, tau pathology generally preceded TDP-43 pathology. Biochemical analysis confirmed the presence of TDP-43 abnormalities in the tau mice, which showed increased levels of high molecular weight, soluble TDP-43 and insoluble full-length and ~35 kD TDP-43. These data demonstrate that the neurodegenerative cascade associated with a primary tauopathy in tau transgenic mice can also promote TDP-43 abnormalities. These findings provide the first in vivo models to understand how TDP-43 pathology may arise as a secondary consequence of a primary proteinopathy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-013-1123-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-3690181 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Springer-Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-36901812013-06-24 Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy Clippinger, Amy K. D’Alton, Simon Lin, Wen-Lang Gendron, Tania F. Howard, John Borchelt, David R. Cannon, Ashley Carlomagno, Yari Chakrabarty, Paramita Cook, Casey Golde, Todd E. Levites, Yona Ranum, Laura Schultheis, Patrick J. Xu, Guilian Petrucelli, Leonard Sahara, Naruhiko Dickson, Dennis W. Giasson, Benoit Lewis, Jada Acta Neuropathol Original Paper Frontotemporal lobar degeneration (FTLD) has been subdivided based on the main pathology found in the brains of affected individuals. When the primary pathology is aggregated, hyperphosphorylated tau, the pathological diagnosis is FTLD-tau. When the primary pathology is cytoplasmic and/or nuclear aggregates of phosphorylated TAR-DNA-binding protein (TDP-43), the pathological diagnosis is FTLD-TDP. Notably, TDP-43 pathology can also occur in conjunction with a number of neurodegenerative disorders; however, unknown environmental and genetic factors may regulate this TDP-43 pathology. Using transgenic mouse models of several diseases of the central nervous system, we explored whether a primary proteinopathy might secondarily drive TDP-43 proteinopathy. We found abnormal, cytoplasmic accumulation of phosphorylated TDP-43 specifically in two tau transgenic models, but TDP-43 pathology was absent in mouse models of Aβ deposition, α-synucleinopathy or Huntington’s disease. Though tau pathology showed considerable overlap with cytoplasmic, phosphorylated TDP-43, tau pathology generally preceded TDP-43 pathology. Biochemical analysis confirmed the presence of TDP-43 abnormalities in the tau mice, which showed increased levels of high molecular weight, soluble TDP-43 and insoluble full-length and ~35 kD TDP-43. These data demonstrate that the neurodegenerative cascade associated with a primary tauopathy in tau transgenic mice can also promote TDP-43 abnormalities. These findings provide the first in vivo models to understand how TDP-43 pathology may arise as a secondary consequence of a primary proteinopathy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-013-1123-8) contains supplementary material, which is available to authorized users. Springer-Verlag 2013-05-11 2013 /pmc/articles/PMC3690181/ /pubmed/23666556 http://dx.doi.org/10.1007/s00401-013-1123-8 Text en © The Author(s) 2013 https://creativecommons.org/licenses/by/2.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Original Paper Clippinger, Amy K. D’Alton, Simon Lin, Wen-Lang Gendron, Tania F. Howard, John Borchelt, David R. Cannon, Ashley Carlomagno, Yari Chakrabarty, Paramita Cook, Casey Golde, Todd E. Levites, Yona Ranum, Laura Schultheis, Patrick J. Xu, Guilian Petrucelli, Leonard Sahara, Naruhiko Dickson, Dennis W. Giasson, Benoit Lewis, Jada Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy |
title | Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy |
title_full | Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy |
title_fullStr | Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy |
title_full_unstemmed | Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy |
title_short | Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy |
title_sort | robust cytoplasmic accumulation of phosphorylated tdp-43 in transgenic models of tauopathy |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690181/ https://www.ncbi.nlm.nih.gov/pubmed/23666556 http://dx.doi.org/10.1007/s00401-013-1123-8 |
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