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Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis

Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causi...

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Autores principales: Ditsworth, Dara, Maldonado, Marcus, McAlonis-Downes, Melissa, Sun, Shuying, Seelman, Amanda, Drenner, Kevin, Arnold, Eveline, Ling, Shuo-Chien, Pizzo, Donald, Ravits, John, Cleveland, Don W., Da Cruz, Sandrine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427168/
https://www.ncbi.nlm.nih.gov/pubmed/28357566
http://dx.doi.org/10.1007/s00401-017-1698-6
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author Ditsworth, Dara
Maldonado, Marcus
McAlonis-Downes, Melissa
Sun, Shuying
Seelman, Amanda
Drenner, Kevin
Arnold, Eveline
Ling, Shuo-Chien
Pizzo, Donald
Ravits, John
Cleveland, Don W.
Da Cruz, Sandrine
author_facet Ditsworth, Dara
Maldonado, Marcus
McAlonis-Downes, Melissa
Sun, Shuying
Seelman, Amanda
Drenner, Kevin
Arnold, Eveline
Ling, Shuo-Chien
Pizzo, Donald
Ravits, John
Cleveland, Don W.
Da Cruz, Sandrine
author_sort Ditsworth, Dara
collection PubMed
description Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43(Q331K) mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43(Q331K) gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-017-1698-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-54271682017-05-26 Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis Ditsworth, Dara Maldonado, Marcus McAlonis-Downes, Melissa Sun, Shuying Seelman, Amanda Drenner, Kevin Arnold, Eveline Ling, Shuo-Chien Pizzo, Donald Ravits, John Cleveland, Don W. Da Cruz, Sandrine Acta Neuropathol Original Paper Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43(Q331K) mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43(Q331K) gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-017-1698-6) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2017-03-29 2017 /pmc/articles/PMC5427168/ /pubmed/28357566 http://dx.doi.org/10.1007/s00401-017-1698-6 Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Paper
Ditsworth, Dara
Maldonado, Marcus
McAlonis-Downes, Melissa
Sun, Shuying
Seelman, Amanda
Drenner, Kevin
Arnold, Eveline
Ling, Shuo-Chien
Pizzo, Donald
Ravits, John
Cleveland, Don W.
Da Cruz, Sandrine
Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis
title Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis
title_full Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis
title_fullStr Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis
title_full_unstemmed Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis
title_short Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis
title_sort mutant tdp-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427168/
https://www.ncbi.nlm.nih.gov/pubmed/28357566
http://dx.doi.org/10.1007/s00401-017-1698-6
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