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dc.contributor.author
Müller Igaz, Lionel Ivan
dc.contributor.author
Kwong, Linda K.
dc.contributor.author
Lee, Edward B.
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Chen Plotkin, Alice
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Swanson, Eric
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Unger, Travis
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Malunda, Joe
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Xu, Yan
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Winton, Matthew J.
dc.contributor.author
Trojanowski, John Q.
dc.contributor.author
Lee, Virginia M. Y.
dc.date.available
2017-02-13T15:51:05Z
dc.date.issued
2011-02
dc.identifier.citation
Müller Igaz, Lionel Ivan; Kwong, Linda K.; Lee, Edward B.; Chen Plotkin, Alice; Swanson, Eric; et al.; Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice; Amer Soc Clinical Investigation Inc; Journal Of Clinical Investigation; 121; 2; 2-2011; 726-738
dc.identifier.issn
0021-9738
dc.identifier.uri
http://hdl.handle.net/11336/12905
dc.description.abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by cytoplasmic protein aggregates in the brain and spinal cord that include TAR-DNA binding protein 43 (TDP-43). TDP-43 is normally localized in the nucleus with roles in the regulation of gene expression, and pathological cytoplasmic aggregates are associated with depletion of nuclear protein. Here, we generated transgenic mice expressing human TDP-43 with a defective nuclear localization signal in the forebrain (hTDP-43-ΔNLS), and compared them with mice expressing WT hTDP-43 (hTDP-43-WT) to determine the effects of mislocalized cytoplasmic TDP-43 on neuronal viability. Expression of either hTDP-43-ΔNLS or hTDP-43-WT led to neuron loss in selectively vulnerable forebrain regions, corticospinal tract degeneration, and motor spasticity recapitulating key aspects of FTLD and primary lateral sclerosis. Only rare cytoplasmic phosphorylated and ubiquitinated TDP-43 inclusions were seen in hTDP-43-ΔNLS mice, suggesting that cytoplasmic inclusions were not required to induce neuronal death. Instead, neurodegeneration in hTDP-43 and hTDP-43-ΔNLS–expressing neurons was accompanied by a dramatic downregulation of the endogenous mouse TDP-43. Moreover, mice expressing hTDP-43-ΔNLS exhibited profound changes in gene expression in cortical neurons. Our data suggest that perturbation of endogenous nuclear TDP-43 results in loss of normal TDP-43 function(s) and gene regulatory pathways, culminating in degeneration of selectively vulnerable affected neurons.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Amer Soc Clinical Investigation Inc
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Tdp-43
dc.subject
Neurodegeneration
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Transgenic Mice
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Dementia
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Neurociencias
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Medicina Básica
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CIENCIAS MÉDICAS Y DE LA SALUD
dc.title
Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2017-02-09T18:23:39Z
dc.journal.volume
121
dc.journal.number
2
dc.journal.pagination
726-738
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Ann Arbor
dc.description.fil
Fil: Müller Igaz, Lionel Ivan. University of Pennsylvania; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
dc.description.fil
Fil: Kwong, Linda K.. University of Pennsylvania; Estados Unidos
dc.description.fil
Fil: Lee, Edward B.. University of Pennsylvania; Estados Unidos
dc.description.fil
Fil: Chen Plotkin, Alice. University of Pennsylvania; Estados Unidos
dc.description.fil
Fil: Swanson, Eric. University of Pennsylvania; Estados Unidos
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Fil: Unger, Travis. University of Pennsylvania; Estados Unidos
dc.description.fil
Fil: Malunda, Joe. University of Pennsylvania; Estados Unidos
dc.description.fil
Fil: Xu, Yan. University of Pennsylvania; Estados Unidos
dc.description.fil
Fil: Winton, Matthew J.. University of Pennsylvania; Estados Unidos
dc.description.fil
Fil: Trojanowski, John Q.. University of Pennsylvania; Estados Unidos
dc.description.fil
Fil: Lee, Virginia M. Y.. University of Pennsylvania; Estados Unidos
dc.journal.title
Journal Of Clinical Investigation
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026736/
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.jci.org/articles/view/44867
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1172/JCI44867
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