Artículo
Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice
Müller Igaz, Lionel Ivan
; Kwong, Linda K.; Lee, Edward B.; Chen Plotkin, Alice; Swanson, Eric; Unger, Travis; Malunda, Joe; Xu, Yan; Winton, Matthew J.; Trojanowski, John Q.; Lee, Virginia M. Y.
Fecha de publicación:
02/2011
Editorial:
Amer Soc Clinical Investigation Inc
Revista:
Journal Of Clinical Investigation
ISSN:
0021-9738
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Palabras clave:
Tdp-43
,
Neurodegeneration
,
Transgenic Mice
,
Dementia
Archivos asociados
Licencia
Identificadores
Colecciones
Articulos(OCA HOUSSAY)
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Citación
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
Compartir
Altmétricas